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Primary Persistent Atrial Fibrillation: A Distinct Arrhythmia Subentity

of an Ablation Population
Torsten Konrad, M.D.; Cathrin Theis, M.D.; Hanke Mollnau, M.D.; Sebastian Sonnenschein, M.D.; Blanca Quesada Ocete, M.D.;
Karsten Bock, M.D.; Thomas Mnzel, M.D.; Thomas Rostock, M.D.

J Cardiovasc Electrophysiol. 2015;26(12):1289-1294.

Abstract and Introduction

Abstract

Primary Persistent AF. Introduction: Persistent atrial fibrillation (persAF) can occur either as a sustained arrhythmia that has
progressed from initially paroxysmal AF or as primary persAF without a history of any spontaneously terminated episode. There
is a paucity of data differentiating between the 2 different persAF entities. Thus, we prospectively evaluated baseline
characteristics, electrophysiological features, and ablation outcome in these 2 patient cohorts.

Methods and results: A total number of 154 consecutive persAF patients (63 10 years, f = 42, longstanding persAF = 60)
were characterized in terms of having primary persAF (P-persAF group) or persAF that secondarily progressed from paroxysmal
AF (S-persAF group). All patients underwent de novo catheter ablation using the stepwise approach. PersAF entities were
characterized by detailed patient history, sequential Holter monitoring, and reports of documented modes of AF conversion,
respectively.

The P-persAF group had a higher number of young patients (<50 years), a shorter AF history, and a higher number of
congestive heart failure. The HATCH score did not differ between the groups. Procedural AF termination rate was significantly
higher in S-persAF than in P-persAF patients (n = 55 [81%] vs. n = 58 [68%], P = 0.043). At 1-year follow-up, the arrhythmia-free
survival after a single procedure was significantly lower in patients with P-persAF (26% vs. 43%, P = 0.016). Categorization to
P-persAF was the strongest independent predictor of arrhythmia recurrence.

Conclusions: P-persAF seems to be a specific arrhythmia entity that is associated with a lower AF-termination rate and a
worse outcome after catheter ablation as compared to S-persAF.

Introduction

Classifications of atrial fibrillation (AF) aim to comprise different features representative for the arrhythmia itself and their clinical
associations in the attempt to characterize distinct entities and, thereby, provide specific therapeutic implications. Therefore, AF
has generally been classified on the basis of clinical, structural and ECG aspects as well as on its temporal patterns.[13] In
clinical practice, the most widely used classification of AF is based on the pattern of occurrence and time of presence:
paroxysmal, persistent, longstanding persistent, and permanent AF.[4] Even though the pattern of AF can change over time, a
classification of the arrhythmia to one of these entities at a given point in time may be clinically relevant to evaluate the optimal
treatment options.

Several studies have evaluated the natural history of patients with AF. Today, it is well recognized that less advanced arrhythmia
entities with short, self-terminating AF episodes may progress to persistent and even permanent forms.[5,6] Co-morbidities and
risk factors influencing the hazard of progression have been extensively studied and a scoring system to determine the patients'
individual propensity to develop arrhythmia progression (HATCH score) was implemented.[6] However, there is a paucity of data
on patients that presented with primarily persistent AF that did not progress secondary from nonsustained forms of the
arrhythmia. Thus, the aim of this study was to characterize patients with primary persistent AF without a history of self-
terminating arrhythmia episodes, with particular regard to epidemiological features and clinical response to a single ablation
procedure.

Methods
Study Population

All consecutive patients with persistent and longstanding AF referred for an interventional treatment were prospectively included
in this study. Paroxysmal and persistent AF was defined in accordance with the current guidelines.[5] All patients were seen in
our outpatient department for cardiac arrhythmias prior to ablation and a systematic clinical evaluation was performed including
12-lead ECG, Holter-ECG, and transthoracic echocardiography, respectively. The patients and/or their referring physician were
asked to provide all available ECG and Holter-ECG recordings along with all previous medical reports. All patients with
depressed cardiac function underwent coronary angiography. Cardiac magnetic resonance tomography was performed in

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selected patients to exclude myocarditis. Only patients with highly symptomatic AF were included, while patients with
documented asymptomatic AF were excluded from study. AF was considered symptomatic in patients with palpitations, exercise
dyspnea and weakness. All patients of both groups had a history of at least 2 elective electrical cardioversion. At consultation in
our outpatient department, a detailed history of all arrhythmia episodes was obtained and correlated with ECG documentation.

On the basis of these parameters, the patients were divided into 2 groups with regard to their onset pattern of AF:

i. "Secondary persistent AF patients" (S-persAF): patients with persistent AF that had progressed secondary from initially
paroxysmal AF. All of these patients had a history of previous episodes of self-terminating AF documented in Holter-
ECG. Moreover, all patients of this group reported on a history of short-lasting palpitations suspicious for AF that did not
require cardioversion.

ii. "Primary persistent AF patients" (P-persAF): all patients in this group had arrhythmia episodes that persisted until
electrical cardioversion terminated AF, exclusively. None of these patients had a history of symptomatic or documented
self-terminating AF. Persistent AF episodes were repeatedly documented to exclude spontaneous intermittent and
asymptomatic events of sinus rhythm (SR). All patients were highly symptomatic and recognized AF immediately at the
occasion of its occurrence.

The study was approved by the institutional review board and ethics committee. All patients provided written informed consent.

Ablation Procedure

All patients underwent a standardized procedure using the stepwise ablation approach as described previously.[7] The operators
were blinded to the categorization results.

The following catheters were introduced via a femoral vein access: (1) A steerable decapolar catheter (Inquiry, IBI, Irvine
Biomedical, Inc., Irvine, CA, USA) was positioned within the coronary sinus (CS); (2) a circumferential decapolar diagnostic
catheter (Lasso, Biosense-Webster, Diamond Bar, CA, USA) for mapping of the pulmonary veins (PV); (3) a nonsteerable
quadripolar diagnostic catheter (Inquiry, IBI) was placed in the right atrial appendage; and (4) a 3.5 mm externally irrigated-tip
ablation catheter (Thermocool, Biosense-Webster). Access to left atrium (LA) was achieved by a single transseptal puncture
with the 2 catheters placed into the left atrium via the same puncture. A single bolus of 50 IU/kg body weight heparin was
administered after transseptal puncture. The activated clotting time was assessed every 30 minutes and maintained within a
range of 250350 seconds. Electrical isolation of the PVs was the first step in all procedures. PV isolation was defined by
elimination or dissociation of PV potentials recorded on the Lasso catheter. After complete electrical PV isolation, mapping and
ablation were routinely continued in the LA. For the purpose of AF cycle length (AFCL) measurement, the Lasso catheter was
placed in the LA appendage. After an initial assessment of AF behavior (local AFCL within the LA, CS and right atrium (RA) and
AFCL gradient between chambers), electrogram-guided ablation targeting specific electrogram patterns and electrogram
behaviors was performed, consisting of continuous electrical activity, high-frequency complex fractionated activity, locally short
AFCL or intermittent local burst activity, temporal activation gradient between the distal and proximal bipoles of the roving
ablation catheter and local spreading of centrifugal activation. Ablation of the CS was performed when the LA AFCL became
longer than the local AFCL in the CS. Mapping and ablation using the same criteria were continued in the RA if AF did not
terminate during LA and CS ablation.

Mapping of atrial tachycardia (AT) was performed using conventional techniques.[8] In the case of macroreentrant ATs, linear
ablation was performed and the endpoint of bidirectional block was assessed and confirmed by differential pacing maneuvers
after restoration of SR. Focal ATs were mapped by assessing the earliest endocardial activation in relation to P-wave onset or, if
P-wave onset could not be clearly identified, to a fixed intracardiac electrogram. After AT termination, no attempt at arrhythmia
re-induction was performed.

In case that AF or AT termination could not be achieved (after an exceedingly long procedure duration of > 4 hours), electrical
cardioversion was performed.

Ablation was performed with a maximum power output of 30 W using an irrigation rate of 1030 mL/min (0.9% saline infused
with the CoolFlow Pump, Biosense-Webster) for the PVs, 35 W and an irrigation rate between 30 and 60 mL/min in the LA, and
up to 30 W in the RA. RF current was applied within the CS with a maximum of 25 W and a manually adjusted irrigation rate to
keep the tip-temperature below 42 C.

The procedural time was defined as the time from the groin puncture to withdrawal of the sheaths.

Follow-Up

All patients were seen regularly every 3 months in our outpatient clinic. Before visits, the patients received at least 2 separate 48
hour Holter-ECGs. A detailed history of the patients' symptoms suggestive for potential arrhythmia recurrences was taken. In the
case of undocumented symptoms suspicious for arrhythmia recurrences, documentation by additional external ECG event
recordings was performed. A documented symptomatic or asymptomatic arrhythmia episode lasting > 30 seconds was defined
as recurrence.

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An initial blanking period of 3 months was accepted. During the blanking period, antiarrhythmic drug treatment was continued at
the discretion of the operator. All antiarrhythmic drugs (excluding betablocker for the treatment of hypertension) were ceased
after the blanking period. Patients with an arrhythmia recurrence after the blanking period were considered procedural failure.

Statistical Analysis

All continuous variables were reported as mean SD and medians with ranges, whereas categorical variables were
summarized as proportions. Categorical variables were compared using the 2-test. Comparison between groups was
performed with either Student t-test or the 2-test. For non-normally distributed variables, the MannWhitney U-test was used. A
P-value of <0.05 was considered to indicate a statistically significant difference. Time to arrhythmia recurrence was estimated
using the KaplanMeier method and compared by the log-rank test. Multivariate analysis by means of a logistic regression
model and stepwise backward selection was performed to identify significant and independent predictors of arrhythmia
recurrence after 6 months. Independent variables were chosen when a P<0.10 emerged on univariate analysis. Variables in the
initial model for arrhythmia recurrence included the history of persistence, total history of AF, duration of current AF-episode,
age, male sex, BMI, history of hypertension, congestive heart failure, coronary artery disease, LA diameter, and left ventricular
ejection fraction. The 95% confidence limits of correlation coefficients were determined by Fisher r-to-z transformation.
Statistical analysis was performed with a statistical software package (SPSS, version 21, IBM, Armonk, NY, USA).

Results
Patient Population

An overall number of 154 consecutive patients with persistent (n = 94, 61%) and longstanding persistent (n = 60, 39%) AF were
identified to meet the inclusion criteria. The study population comprised 42 (27%) females and the mean age was 63 10 years.

Characterization of Persistent AF Subentities

In the overall study population, more than half of the patients (n = 86, 56%) met the criteria for the classification of primary
persistent AF, whereas 68 (44%) had persistent AF that had secondary progressed from paroxysmal AF. Although the mean age
did not differ between the 2 groups, significantly more patients with P-persAF were younger than 50 years at the time of ablation
(). Patients with P-persAF were also characterized by a shorter history of AF (30 27 vs. 53 39 months, P = 0.001) and a
lower number of failed antiarrhythmic drug trials prior to ablation. Moreover, deterioration of left ventricular function with both AF-
related cardiomyopathy and congestive heart failure was significantly more often observed in patients with P-persAF. Notably, no
significant difference between both AF entities was observed in the HATCH score[6] (P-persAF 1.62 vs. S-persAF 1.56 points; P
= 0.35). The mean heart rate did not differ between the 2 groups (82 13 vs. 84 14 bpm, P = 0.188). The detailed baseline
characteristics and comparisons are presented in . Furthermore, no significant differences were observed between the 2 groups
in terms of antiarrhythmic and heart failure medication ().

Table 1. Comparison of Baseline Characteristics

P-persAF S-persAF P
Number 86 68
Age, years 6211 659 0.25
Age < 50, years 9 (11) 2 (3) 0.023
Female, n (%) 21 (24) 21 (31) 0.67
Hypertension, n (%) 60 (70) 52 (76) 0.42
Sleep apnea syndrome, n (%) 11 (13) 9 (13) 0.3
History of stroke, n (%) 4 (5) 2 (3) 0.13
Body mass index, kg/m2 27.53.7 28.03.8 0.31
HATCH score 1.61.1 1.61.2 0.354
Congestive heart failure, n (%) 27 (31) 13 (19) 0.042
AF-related heart failure, n (%) 19 (22) 9 (13) 0.048
Coronary artery disease, n (%) 14 (16) 12 (18) 0.23
Failed antiarrhythmic drugs 1.20.9 1.50.8 0.043
History of AF, months 3027 5239 0.001
Duration of uninterrupted AF 9.27.3 11.513.3 0.07

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Left atrial diameter, mm 5411 507 0.085
Left ventricular ejection fraction, % 5413 5912 0.015

P-persAF = primary persistent atrial fibrillation; S-persAF = secondary persistent atrial fibrillation.

Table 1. Comparison of Baseline Characteristics

P-persAF S-persAF P
Number 86 68
Age, years 6211 659 0.25
Age < 50, years 9 (11) 2 (3) 0.023
Female, n (%) 21 (24) 21 (31) 0.67
Hypertension, n (%) 60 (70) 52 (76) 0.42
Sleep apnea syndrome, n (%) 11 (13) 9 (13) 0.3
History of stroke, n (%) 4 (5) 2 (3) 0.13
Body mass index, kg/m2 27.53.7 28.03.8 0.31
HATCH score 1.61.1 1.61.2 0.354
Congestive heart failure, n (%) 27 (31) 13 (19) 0.042
AF-related heart failure, n (%) 19 (22) 9 (13) 0.048
Coronary artery disease, n (%) 14 (16) 12 (18) 0.23
Failed antiarrhythmic drugs 1.20.9 1.50.8 0.043
History of AF, months 3027 5239 0.001
Duration of uninterrupted AF 9.27.3 11.513.3 0.07
Left atrial diameter, mm 5411 507 0.085
Left ventricular ejection fraction, % 5413 5912 0.015

P-persAF = primary persistent atrial fibrillation; S-persAF = secondary persistent atrial fibrillation.

Table 2. Comparison of Antiarrhythmic and Heart Failure Medication in Patients of Both Groups

P-persAF n = 86 S-persAF n = 68 P
Beta-blockers, n (%) 75 (87) 61 (90) 0.299
ACE/ARB inhibitors, n (%) 63 (73) 44 (64) 0.103
Spironolactone, n (%) 9 (11) 5 (8) 0.189
Amiodarone, n (%) 11 (13) 14 (20) 0.144
Electrophysiological Characterization

All patients presented in spontaneous AF at the beginning of the procedure. The baseline AFCL did not differ between the 2
different persistent AF entities. However, the desired endpoint of procedural AF termination was achieved in a significantly lower
number of patients with P-persAF (68 vs. 81%, P = 0.043). Despite a significantly lower AF termination rate, the mean
procedural and fluoroscopy times as well as the mean total duration of RF delivery was significantly longer in patients with P-
persAF, both indicating a more complex procedure ().

Table 3. Comparison of Electrophysiological Data

P-persAF n = 86 S-persAF n = 68 P
Baseline AFCL in LAA, milliseconds 16823 17022 0.28
Baseline AFCL in RAA, milliseconds 17526 17427 0.34
Total procedure time, minutes 19650 18850 0.19

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Fluoroscopy time, minutes 4413 3913 0.005

Radiofrequency ablation time, minutes 7018 6420 0.018
Procedural AF termination 59 (68) 55 (81) 0.043

AFCL = atrial fibrillation cycle length; LAA = left atrial appendage; RAA = right atrial appendage.

Clinical Outcome After Ablation

All patients were eligible for outcome analysis. During a follow-up duration of 1 year, significant more patients in the S-persAF
group were free of arrhythmia recurrences than those in the P-persAF group (43 vs. 26%, P = 0.016) (Fig. 1). The type of
arrhythmia recurrences did not differ between both groups (AT: 43 [63%] vs. 57 [66%], P = 0.37; persistent AF: 12 [18%] vs. 15
[17%], P = 0.49; paroxysmal AF: 12 [18%] vs. 15 [17%], P = 0.47). The number of patients on continued antiarrhythmic drug
therapy did not show significant differences (13 [19%] vs. 18 [21%], P = 0.34; patients on amiodarone: 11 [16%] vs. 14 [16%], P
= 0.87).

Figure 1.

KaplanMeier survival curve after ablation.

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Patients with P-persAF underwent a total number of 1.7 0.7 procedures whereas S-persAF patients had a total number of 1.5
0.6 procedures (P = 0.12). After a median overall follow-up duration of 12.5 0.7 months after the final procedure, 71% (n =
61) of the P-persAF patients and 78% (n = 52, P = 0.33) of the S-persAF patients were free of arrhythmia recurrences.

Predictors of Arrhythmia-free Survival

Patient characteristics and history of AF persistence were evaluated in uni- and multivariate regression analysis. In univariate
regression analysis, classification to P-persAF, duration of persAF history, more severely dilated LA, depressed LV function, and
congestive heart failure were associated with a worse outcome after ablation. However, multivariate analysis revealed only
classification to P-persAF, depressed LV function and duration of persAF history as independent predictors of arrhythmia
recurrences after ablation. Of note, the strongest predictor was the classification to P-persAF ().

Table 4. Uni- and Multivariate Regression Analyses for Predictors of Arrhythmia-Free Survival

Univariate regression analysis

Baseline Variable P Hazard Ratio 95% Confidence Interval
Classification to P-persAF 0.025 2.163 1.0934.280
Duration of persAF-history 0.028 1.997 1.0343.874
LA diameter 0.040 1.38 1.0083.982
LVEF 0.030 0.823 0.7860.936
Congestive heart failure 0.042 1.32 1.0674.628
Multivariate regression analysis
Classification to P-persAF 0.039 2.051 1.0583.978
LVEF 0.040 0.931 0.8820.989
Duration of persAF-history 0.038 1.896 1.0643.766

Discussion
Main Findings

This prospective study provides new information on a distinct subentity of primary persistent AF in an ablation population: first,
P-persAF is more often associated with structural and functional deterioration of left ventricular function. Second, although P-
persAF patients did not demonstrate different AFCL as compared to S-persAF patients, the procedural AF termination rate was
significantly lower in P-persAF patients. Third, the arrhythmia-free outcome after a single AF ablation procedure is limited in P-
persAF. Fourth, the presence of P-persAF and duration of AF history were identified as independent predictors for outcome after
a single ablation. And finally, this study revealed young patients with P-persAF as a specific subgroup that is associated with
distinct baseline characteristics and an inferior benefit from catheter ablation.

Pathophysiological Considerations of Persistent AF Evolution

More than 20 years ago, the group of Allessie implemented the groundbreaking paradigm of "AF begets AF",[9] suggesting that
electrical changes promoting arrhythmia perpetuation are induced by the presence of AF itself. Since electrical remodeling (the
"first factor") requires a rather short time (23 days) to generate a significantly altered electrophysiological state in the atria, "AF
domestication" with a self-sustaining arrhythmia was observed only at 12 weeks after initiation,[9] indicating the presence of a
slower acting "second factor" facilitating AF progression.[10,11] These data have triggered both animal and human studies that
thoroughly investigated mechanisms potentially involved in the self-maintaining process of AF. It has been shown that with the
presence of AF, more gradually developing alterations occur (atrial myocyte hypertrophy, changes in expression of connexins
and gap junctions, alterations in the extracellular matrix) that form a substrate capable to maintain AF over time.[11] However,
the mechanisms that make the atria capable to incessantly sustain AF from the very first moment are still not investigated. Thus,
the key question remains unanswered: what is the initiator/promoter acting prior to the well-investigated mechanisms of the "first
and second factor" of AF progression? Hypothetically, an initial trigger may arise from a PV focus (facilitated by intermittent
atrial/PV stretch and vagal conditions), thereby starting a cascade of electrical and subsequent structural atrial alterations. It has
been previously demonstrated that even in humans devoid of a history of AF, the electrical properties of the PVs significantly
change after the presence of merely 15 minutes of artificially induced AF, associated with an enhanced susceptibility of AF
induction.[12] These PV alterations may induce electrical activities in other PVs with a "ping-pong" effect resulting in continuous
PV activity as the trigger for the "first factor" of AF progression to a persistent episode. Then, other conditions that facilitate an
acceleration of the "second factor" mechanisms are required that prevent the AF to terminate after the electrical activity from the
PVs expire. These rather "occult" conditions may perform on the basis of inflammatory processes and abnormally enhanced or
vulnerable cardiac ion-channel activities. However, further studies are required to explore potential mechanisms of early un-
interrupted AF perputation.

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In our study population, the HATCH score, a well-defined scoring system to evaluate the risk of arrhythmia progression to
persistent AF, did not differ between the 2 groups. Thus, clinical parameters predicting AF progression are not appropriate to
define P-persAF patients and therefore may not attribute to the development of this particular arrhythmia entity. On the other
hand, the number of younger patients (age < 50 years) was significantly higher in the P-persAF group, potentially indicating a
genetic or epigenetic basis. Teh et al.[13] described progressive electrical substrate remodeling despite successful ablation
indicating that AF may occur as an electrical disorder in a more extensive structural atrial disease.[14] Accordingly, Kottkamp[14]
proposed the term "fibrotic atrial cardiomyopathy" for a subgroup of patients with an arrhythmia-independent structural and
electrical cardiomyopathy where AF is merely a subdiagnosis.

Clinical Implications

Clinical classifications of AF are used to share standardized communication on the magnitude and persistence of the arrhythmia
in order to define the appropriate therapy of the individual patient. Moreover, AF classifications attempt to provide a
categorization in terms of the stage of the disease with progression from the paroxysmal form without or only mild alterations
toward longstanding persistent and permanent AF that habitually are associated with complex electrical and structural
abnormalities of the atria. However, the current classifications of AF neither correlate with different stages of structural changes
of the atria nor provide appropriate information on the mechanisms of progression.[3,15] In this study of an ablation population,
we characterized a distinct subentity of persistent AF that did not progress secondary from initially self-terminating AF.
Additionally, significantly more P-persAF patients suffered from functional or structural deterioration of cardiac function. Thus, a
more detailed differentiation of patients with persAF in terms of its onset patterns as well as its association with morphological
changes may help to define the arrhythmia more accurately and thereby provide more information on the potential outcome of
an ablation procedure.

The data of our study demonstrate that outcome expectations are not collectively uniform in the overall population of patients
with persAF. While co-morbidities such as congestive heart failure and coronary artery disease are well known to significantly
influence long-term outcomes after AF ablation, the duration of uninterrupted persistent AF has more recently emerged as a
crucial factor influencing the ablation success.[7,16,17] However, the results of our study indicate that even the pattern of
persistent AF onset impacts the response to ablation, including the ability to terminate AF and clinical outcome during follow-up.
Thus, the differentiation between P-persAF and S-persAF may help in the evaluation of the most appropriate therapeutic
regimen. Moreover, it may be helpful in patient selection and consenting, particularly regarding the individual expectation of
potentially beneficial and nonbeneficial prognoses of rhythm control strategies.

Limitations

The main limitation of the study is the inability to monitor patients prior to the first documented symptomatic episode of AF.
However, this limitation is inherent to the study issue of investigating patients with the first documented symptomatic episode of
persistent AF. The only reliable method to receive continuous cardiac monitoring prior to the first occurrence of a persistent AF
episode would be available from cardiac rhythm devices featured with a Holter function initially implanted in patients without AF.
In this study, we did not have the opportunity to continuously monitor the patients with implantable devices. It cannot be
completely excluded that subclinical episodes did occur prior to the diagnosis of primary persistent AF. Thus, misinterpretations
of AF categorized as being an uninterrupted persistent episode cannot be excluded. However, we only included patients with
highly symptomatic AF and with a comprehensively documented arrhythmia history to minimize risk of inappropriately
categorized AF.

In the presented study, we did not perform functional or morphological characterization by obtaining voltage maps or cardiac
magnetic resonance imaging. Further studies using more sophisticated imaging techniques to characterize potential differences
in the substrates of these patient cohorts are mandatory and desired.[14]

The study results are derived from an ablation population and not from all-comers with AF. Thus, the findings of our study may
be different for other AF populations.

In this study, we did not perform any genetic evaluation. Further studies are desired to evaluate a potential genetic
predisposition in the subgroup of patients with P-persAF.

Conclusions

In a substantial number of patients scheduled for an ablation procedure for persAF, the persistent form of the arrhythmia is not a
result of a progressive arrhythmogenic evolution from an initially paroxysmal form. In the studied ablation population, patients
with primarily persistent AF without any self-limiting episode represent a distinct arrhythmia subentity characterized by a
younger patient age, higher association with functional and structural deterioration of left ventricular function, and a limited
response to catheter ablation.

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