Atrial Fibrillation Ablation Outcome Is Predicted by …2013/12/20 · Damal, Brent Wilson, Josh Cates, Alexis Harrison, Ravi Ranjan, Nathan S. Burgon, Tom Greene, Dan Christopher

Kim, Edward V.R. DiBella, Dennis Parker, Rob S. MacLeod and Nassir F. MarroucheDanDamal, Brent Wilson, Josh Cates, Alexis Harrison, Ravi Ranjan, Nathan S. Burgon, Tom Greene,

Christopher McGann, Nazem Akoum, Amit Patel, Eugene Kholmovski, Patricia Revelo, KavithaAtrial Fibrillation Ablation Outcome Is Predicted by Left Atrial Remodeling on MRI

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DOI: 10.1161/CIRCEP.113.000689

1

Atrial Fibrillation Ablation Outcome Is Predicted by Left Atrial

Remodeling on MRI

Running title: McGann et al.; AF Ablation Outcome Predicted by LGE-MRI

Christopher McGann, MD1,2,3*; Nazem Akoum, MD1,2*; Amit Patel, MD3;

Eugene Kholmovski, PhD1,4; Patricia Revelo, MD, PhD6; Kavitha Damal, PhD1;

Brent Wilson, MD, PhD1,2,3; Josh Cates, PhD1,5; Alexis Harrison, MD1,2; Ravi Ranjan, MD1,2;

Nathan S. Burgon BSc1; Tom Greene, PhD7; Dan Kim, PhD1,4; Edward V.R. DiBella, PhD1,4;

Dennis Parker, PhD1,4; Rob S. MacLeod, PhD1,5; Nassir F. Marrouche, MD1,2

1Comprehensive Arrhythmia Research and Management Center (CARMA), 2Division of Cardiology,3Department of Surgery, 4Department of Radiology, 5Scientific Computing and Imaging Institute, Bioengineering, 6Department of Pathology, 7Division of Epidemiology,University of Utah Health

Sciences Center, Salt Lake City, UT *contributed equally

Correspondence:

Christopher McGann, MD

Departments of Internal Medicine and Radiology

Comprehensive Arrhythmia Research and Management Center (CARMA)

University of Utah Health Sciences Center

30 North 1900 East

Salt Lake City, UT 84132

Tel: 801 585-2341

Fax: 801 587-5874

E-mail: [email protected]

Journal Subject Codes: [30] CT and MRI, [22] Ablation/ICD/surgery

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DOI: 10.1161/CIRCEP.113.000689

2

Abstract:

Background - While catheter ablation therapy for atrial fibrillation (AF) is becoming more

common, results vary widely and patient selection criteria remain poorly defined. We

hypothesized that late gadolinium enhancement magnetic resonance imaging (LGE-MRI) can

identify left atrial (LA) wall structural remodeling (SRM) and stratify patients who are likely or

not to benefit from ablation therapy.

Methods and Results - LGE-MRI was performed on 426 consecutive AF patients without

contraindications to MRI and before undergoing their first ablation procedure and on 21 non-AF

control subjects. Patients were categorized by SRM stage (I-IV) based on percentage of LA wall

enhancement for correlation with procedure outcomes. Histological validation of SRM was

performed comparing LGE-MRI to surgical biopsy. A total of 386 patients (91%) with adequate

LGE-MRI scans were included in the study. Post-ablation, 123 (31.9%) experienced recurrent

atrial arrhythmias over one-year follow-up. Recurrent arrhythmias (failed ablations) occurred at

higher SRM stages with 28/133 (21.0%) stage I, 40/140 (29.3%) stage II, 24/71 (33.8%) stage

III, and 30/42 (71.4%) stage IV. In multi-variate analysis, ablation outcome was best predicted

by advanced SRM stage (hazard ratio (HR) 4.89; p<0.0001) and diabetes (HR 1.64; p=0.036)

while increased LA volume and persistent AF were not significant predictors. LA wall

enhancement was significantly greater in AF patients vs. non-AF controls (16.6±11.2% vs.

3.1±1.9%, p<0.0001). Histological evidence of remodeling from surgical biopsy specimens

correlated with SRM on LGE-MRI.

Conclusions - Atrial SRM is identified on LGE-MRI and extensive LGE 30% LA wall

enhancement) predicts poor response to catheter ablation therapy for AF.

Key words: atrial fibrillation arrhythmia, catheter ablation, magnetic resonance imaging, remodeling, outcome

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DOI: 10.1161/CIRCEP.113.000689

3

Background

Atrial fibrillation (AF) is the most common sustained arrhythmia in clinical practice with its

prevalence increasing along with the age of the population 1,2. It occurs in 1-2% of the general

population and the lifetime risk for development of AF in the Framingham cohort was 25%

among those over 40 years of age 3. The clinical consequences of AF are well known and

include increased risk of heart failure, stroke, and death 4. Increased risk for the development of

AF has been associated with factors such as age, hypertension, and obesity 5-9 but more specific

and early markers for disease could have important clinical impact.

Several large clinical trials have shown no significant benefits of rhythm control

strategies using anti-arrhythmic medications over rate control alone in the treatment for AF 10-12.

As a result, the morbidity and mortality associated with AF remains largely unchanged along

with the associated medical costs, which are estimated to be greater than 6 billion dollars

annually in the United States and Europe alone. Given the limited utility of anti-arrhythmic

medications, there has been growing interest in the treatment of AF with catheter ablation due to

improvements in efficacy and outcomes 13-17. However, reported success rates for AF ablation

vary widely in the published literature ranging from 40-70% and suggest a need for better patient

selection criteria 18.

Atrial structural remodeling with associated interstitial fibrosis is well described in

patients with AF in histological studies 19-23. Tissue examination of the LA has also confirmed

the presence of fibrosis in regions of low voltage tissue 24. Whether fibrotic transformation of

atrial myocardium is a cause or consequence of AF in patients with cardiovascular disease

remains unclear. Studies have demonstrated that AF is associated with electrical, contractile,

and structural remodeling (SRM) in the LA that contributes to the persistence and sustainability

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, the morbidity and mortality associated with AF remains largely unchanged alon

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DOI: 10.1161/CIRCEP.113.000689

4

of the arrhythmia 25. It has also been shown that the end result of this remodeling process is loss

of atrial myocytes and increased collagen content and hence fibrosis of the LA wall. Previous

small electrophysiology and imaging studies have shown low voltage and fibrotic LA tissue as

independent predictors of procedure outcome and suggest that an accurate and reliable measure

of LA fibrosis may improve clinical decision making 26-27. Better patient selection criteria would

be expected to improve procedure outcomes while reducing costs and avoiding potential

complications in those unlikely to benefit from ablation.

In the current study, we tested the hypothesis that LGE-MRI can provide a measure of

LA wall SRM in patients with AF and will stratify those patients who are likely or not to benefit

from catheter ablation procedures.

Methods

Patients. The study population included 426 consecutive patients without contraindications to

MRI who underwent their first AF ablation procedure, 21 control subjects, and 9 AF patients and

1 non-AF patient who had LA wall biopsies during cardiothoracic surgical procedures. The

control group was comprised of a series of consecutive patients presenting for routine screening

colonoscopy (21 patients), none of whom had a history of AF. The AF study population was

recruited from the AF clinic from December 2006 to May 2009 with three-year follow-up.

Statistical analysis of the data focuses on the 1-year follow-up when recurrences were based on

routine, scheduled Holter monitoring in all patients (see details of follow-up below). The control

and surgical groups were recruited from August 2010 to December 2011. Written informed

consent was obtained on all patients and the protocol was approved by the Institutional Review

Board at the University of Utah and was compliant with the Health Insurance Portability and

Accountability Act (HIPAA) of 1996.

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DOI: 10.1161/CIRCEP.113.000689

5

Magnetic resonance imaging. All subjects underwent initial 3D LGE-MRI scanning to

determine the degree of LA wall SRM regardless of the rhythm at the time of scanning.

Adequate images for quantification of LA wall SRM was obtained in 386/426 patients in the AF

ablation cohort (91%), all control subjects, and all surgical patients. High-resolution LGE

images of LA were acquired approximately 15 minutes after injection of 0.1 mmol/kg

gadolinium contrast (Multihance, Bracco Diagnostics Inc., Princeton, NJ) using a 3D respiratory

navigated, inversion recovery prepared GRE pulse sequence with specific parameters published

previously 27-29. The specific parameters for MR scanning at 1.5T vs. 3T are provided in the

supplemental materials. Briefly, for this 3D respiratory navigated, ECG-gated, inversion

recovery prepared GRE pulse sequence, an inversion preparation was applied every heart beat

and fat saturation was applied immediately before data acquisition. The voxel size = 1.25 x 1.25

x 2.5 mm on both 1.5T and 3T scanners.

Though pre-scan ECG’s were not routinely obtained, the rhythm status is always clarified

at the time of MRI scanning by the technologist and reading physician by use of the ECG gating

from the scanner and if necessary by evaluating the cine images. By these criteria, 67% of the

study patients appeared in sinus rhythm at the time of scanning. Of the 40 patients with

inadequate scans, artifacts due to patient motion, marked arrhythmias, or gating problems were

the main contributing factors. Scanning was performed on a 1.5 Tesla Avanto (286 patients) or a

3 Tesla Verio (100 patients) MR scanner (Siemens Healthcare, Erlangen, Germany).

LGE-MRI assessment of LA structural remodeling. LA wall volumes were manually

segmented by three trained observers from the LGE-MRI images using the Corview image

processing software (MARREK Inc., Salt Lake City, UT). The MRI scans were de-identified and

observers were blinded to whether scans were performed on control subjects, AF patients, or

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DOI: 10.1161/CIRCEP.113.000689

6

surgical patients. The protocol for segmentation proceeded as follows. First, the endocardial

border of the LA was defined, including an extent of pulmonary vein (PV) sleeves, by manually

tracing the LA-PV blood pool in each slice of the LGE-MRI volume. Next, the endocardial

segmentation was morphologically dilated and then manually adjusted to create an assessment of

the boundary of the epicardial LA surface. Finally, the endocardial segmentation was subtracted

from the epicardial segmentation to define a wall segmentation, which was manually edited to

exclude the mitral valve and PVs. Thus, the resulting LA wall segmentation included the 3D

extent of both the LA wall and the antral regions of the PVs (Figure 1).

Quantification of LA remodeling was obtained using the methods previously described

with the addition of software implemented in Corview to improve determination of MRI

intensity values29. Typically, enhancement values are found to be in the range of 2-4 standard

deviations from the mean value. Once the threshold has been determined, the percentage of

enhancement is calculated as the number of voxels in the LA wall segmentation with values

above the threshold divided by the total number of voxels in the LA wall segmentation. The

study patients were then assigned to one of 4 SRM categories based on LA wall enhancement as

a percentage of the total LA wall volume with stage I defined as <10%, stage II 10-20%, stage

III 20- Additional details for methods for quantification of LA

remodeling are provided in the supplemental materials.

Ablation procedure and follow-up. The details of the PV isolation in addition to posterior wall

and septal debulking has been described elsewhere 30. A 10-pole circular mapping Lasso catheter

and a 3.5 mm Thermocool ablation catheter (Biosense Webster, Diamond Bar, CA) were used

and radiofrequency energy was delivered with 50 Watts at a catheter tip temperature of 50 °C for

5 seconds, guided by electrogram abolition recordings. Post-ablation, recurrences in year one

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DOI: 10.1161/CIRCEP.113.000689

7

were determined by 8 day Holter monitoring performed on patients at 3, 6, and 12 months,

patient reporting, and all ECG data. In years 2-3, follow-up was based on symptom-guided

Holter monitoring and ECG data during clinic follow-up. Atrial arrhythmia recurrence following

ablation was defined using the Heart Rhythm Society consensus document on catheter and

surgical ablation of AF18,31, and required the presence of 30 seconds of atrial arrhythmia

following a 90-day blanking period. Additional details are provided in the supplemental

materials.

Surgical biopsies and histochemical stains. Myocardial tissue was obtained from the LA at the

time of cardiac surgery in 9 patients with AF and one non-AF patient. All patients underwent

cardiac MRI/MRA scans prior to surgery. The surgeon obtaining the biopsy specimens marked

the biopsy location on an interactive 3D MRA of the LA for each subject, which was then

overlaid on the 3D LGE-MRI to correlate the surgical biopsy site with LA wall tissue on MRI.

The LA biopsy tissue was formalin-fixed and paraffin embedded. Evaluation for collagen

content was performed using Masson’s trichrome stain. Details of whole-field digital

microscopy32 is provided in the supplemental materials.

Statistics. Statistical analysis was performed using STATA12 (Statacorp, College Station, Tx).

LA wall SRM was reported as a continuous variable with a mean +/- standard deviation. Other

continuous variables included age, LA volume and left ventricular ejection fraction. Categorical

variables included gender, and medical comorbidities. An unpaired two-sided Student’s t-test

assuming unequal variences was used to compare means between controls and AF patients and

ANOVA with the Bonferroni correction was used for multiple means comparison between SRM

groups. A Chi-squared test was used to evaluate differences in categorical variables across

different stages. A Fisher's exact test was used to evaluate differences between the AF group and

obtained from the e LALALALA

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DOI: 10.1161/CIRCEP.113.000689

8

the control group. Survival analysis using Cox proportional hazards model was used to identify

uni-variate, multi-variate recurrence predictors. Statistical interaction was examined by including

interaction terms, specifically for clinical variables correlated with atrial SRM. The interaction

terms did not alter the results of statistical association and are not displayed. A p-value less than

0.05 was considered statistically significant. Interobserver variability was calculated using

Pearson’s correlation coefficient.

Results

Study patients and association with SRM stages. A comparison of baseline characteristics of

AF patients across SRM stages is provided in Table 1. AF patients distributed into the four

SRM categories based on the percentage of LA wall enhancement on LGE-MRI as follows: 133

(34.5%) stage I, 140 (36.3%) stage II, 71 (18.4%) stage III, and 42 (10.9%) stage IV. Advanced

SRM stage was associated with increased LA volume index. When comparing SRM stage

versus classification according to AF clinical phenotypes, the prevalence of persistent AF

increased with higher SRM stage while the prevalence of paroxysmal AF decreased. However,

for any individual patient, SRM stage was not predicted by clinical phenotype alone as each

stage showed a heterogeneous mix of phenotypes. Also noteworthy, within our study population,

we found 13 patients with long standing persistent AF of great than 1 year. The average fibrosis

for patients categorized this way was 19.5 ±21.6 vs. 18.7 ±11.5 for persistent AF (p=0.9).

However, there were simply not enough patients in the long-standing persistent group to deduce

any relevance between these two groups. Figure 2 shows representative examples of patients

from each SRM stage on LGE-MRI.

Study patients compared to control groups. The AF study patients were compared to a control

group, without history of AF, consisting of a series of consecutive patients presenting for routine

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DOI: 10.1161/CIRCEP.113.000689

9

screening colonoscopy. LA SRM with percent wall enhancement on LGE-MRI was significantly

greater in the AF patient group when compared to the control group (16.6±11.2% vs. 3.1±1.9%,

p<0.0001). While the AF patients were dispersed across all SRM stages (as noted above), all

control patients were categorized in stage I. Comparisons of other characteristics between AF

patients and controls showed that LA volume was significantly increased in the AF group

compared to the control group (103±41 ml vs. 62±21 ml; p<0.0001). AF patients were also

significantly older and had a higher prevalence of hypertension. A detailed summary of baseline

characteristics of these groups is provided in Table 2.

Predictors of AF ablation outcome. All 386 patients underwent a single ablation procedure for

treatment of AF and 123 (31.9%) experienced recurrent atrial arrhythmias at one-year follow-up.

Kaplan Meier analysis showed recurrent arrhythmias (failed ablations) occurred in patients with

higher SRM scores with 28/133 (21.0%) in stage I, 41/140 (29.3%) in stage II, 24/71 (33.8%) in

stage III, and 30/42 (71.4%) in stage IV. For those who experienced recurrent arrhythmia within

the first year of follow-up, the median time to recurrence was 142 days. The strong association

between atrial SRM stage and arrhythmia recurrence following ablation therapy is shown

graphically in Figure 3.

We performed univariate and multivariate analysis to identify significant predictors of

arrhythmia recurrence. In the univariate analysis, LA volume increase for each 10 ml/m2 (HR

1.16;p=0.0001), age for each 10-year increase (HR 1.22, p=0.011), hypertension (HR 1.61;

p=0.016), diabetes (HR 1.80; p=0.006), and persistent AF (HR 1.47; p=0.014) were associated

with arrhythmia recurrence. Compared to patients with stage I SRM, stage IV patients had the

highest risk of arrhythmia recurrence (HR 5.47; p<0.0001) followed by stage III (HR 1.65;

p=0.069). In the multivariate model, SRM stage IV was associated with the highest risk of

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DOI: 10.1161/CIRCEP.113.000689

10

recurrence (HR 4.89 compared to SRM stage I; p<0.0001). Diabetes was another significant

predictor of arrhythmia recurrence (HR 1.64; p=0.036). The results of the univariate and

multivariate Cox regressions are summarized in Table 3.

After the first year, arrhythmia recurrence was diagnosed based on patient symptom-

guided Holter monitoring and ECG data during clinic follow-up for two additional years. When

we analyze the data over the 3 year period (mean follow-up of 746±428 days), we found that 169

patients (43.8%) experienced recurrent atrial arrhythmias . Similar to the one-year outcomes,

recurrent arrhythmias occurred in patients with higher SRM scores with 44/133 (33.1%) in stage

I, 58/140 (41.4%) in stage II, 34/71 (47.9%) in stage III, and 33/42 (78.6%) in stage IV.

Histologic basis for LA wall fibrosis. Tissue characterization of the LA wall on LGE-MRI

correlated with histology from surgical biopsy specimens. A total of 14 biopsies were taken from

the 10 surgical patients with histories of AF. Nine biopsy locations showed evidence of

significant interstitial fibrosis on Masson’s trichrome staining and 5 locations showing normal

LA wall tissue or minimal collagen staining. LA wall biopsies demonstrating tissue fibrosis

matched with regions of LA wall enhancement on MRI, while normal biopsy tissue

corresponded with non-enhanced regions on MRI. Furthermore, in a surgical patient without AF

and with normal sized LA, no significant atrial wall enhancement was seen on LGE-MRI and

biopsy confirmed tissue without significant interstitial fibrosis (Figure 4).

Interobserver reproducibility. Atrial fibrosis on MRI scans was analyzed and quantified by

three blinded observers on a subset of 170 patients randomly selected from the entire cohort. The

calculated mean fibrosis values between the three observers were not significantly different and

the correlation coefficients ranged from 0.79 to 0.97, indicating a high degree of reproducibility.

The high degree of correlation reflects the good scan quality visualization of the LA wall as well

th 44/133 (3( 3.1%%)))) ininini

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with histology from sur cal biopsy specimens. A total of 14 biopsies were taken

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interstitial fibrosis on Masson’s trichrome staining and 5 locations showing norm

ss e or minimal collagen staining LA all biopsies demonstrating tiss e fibrosi

basasasasisisisis ffforororr LLLA AA wwaww ll fibrosis. Tissue charararacaca terization of f the eee LLALL wall on LGE-MR

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DOI: 10.1161/CIRCEP.113.000689

11

as the experience of the operators in our lab who perform these tracings on a regular basis with

the aid of computer processing tools.

Discussion

We report that LGE-MRI can detect SRM in patients with AF as healthy atrial myocardium

becomes fibrotic. For catheter ablation of AF, restoration of sinus rhythm is shown significantly

less likely as the remodeling process advances. These findings suggest that MRI can improve

the selection process and outcome for patients being considered for AF ablation procedures.

The results here build on previous work showing LGE-MRI an important tool in the

evaluation of LA fibrosis 26,27,29,33. Though LGE-MRI is a well-established method for

characterizing fibrosis and tissue remodeling in the ventricle 34-36, limitations in spatial resolution

have made imaging the LA wall more challenging. Recent advancements in navigated 3D MR

imaging now yield greater signal and improved resolution with the ability to locate and quantify

atrial remodeling. Data here lend validation of the LA remodeling process on LGE-MRI with

clear distinctions between control and AF patients. Specifically, the AF patient cohort

demonstrated a greater than four fold increase in percentage of LA wall enhancement than the

control group. Furthermore, we show that LA wall biopsy specimens with varying degrees of

interstitial fibrosis correlate with findings on LGE-MRI in AF patients. While previous surgical

studies have demonstrated LA SRM on histological examination of biopsies from AF patients

23,37-38, we report that tissue enhancement on LGE-MRI reflects SRM changes. These results

support the use of MRI for non-invasive assessment of the remodeling process.

The amount of LA wall fibrosis on LGE-MRI strongly correlates with AF ablation

outcome, which is the central finding in this study. Arrhythmia recurrence is significantly higher

when 30% fibrosis (IV patients) is present on pre-procedure MRI scans. Scores below 30%

p

n imi popopoportrtrtrtanananant tt t totototoolololol iiiin nnn ththhheee

of LA fibrosis Though LGE MRI is a well established method for

z o

imaging the LA wall more challenging. Recent advancements in navigated 3D

ow yield greater signal and improved resolution with the ability to locate and qua

deling. Data here lend validation of the LA remodeling process on LGE w

of LAAA fffibibbrooosissss . Though LGE-MRRRI is a well-estabblilililished method for

zingngngng fibrosis ananandd tiiisssss ueueueue rrrremememe ododododelelele inininngg ininin thhhe vveentrtrrriciciclelelee 34333 ---3336, lililimmmittatiiononono s ininini ssspapapatiiialalala rrrreesee o

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DOI: 10.1161/CIRCEP.113.000689

12

identify patients far more likely to benefit from catheter ablation procedures. In multivariate

analysis, SRM stage was clearly the strongest predictor of ablation outcomes. Patients with

30% enhancement on MRI (SRM stage IV) demonstrated poor procedure outcomes with a

greater than 70% failure rate. These data support prior studies showing pre-existing low voltage

tissue and scarring in the LA determined invasively during electrophysiology studies are

independent predictors of ablation procedure failure and arrhythmia recurrence39. The presence

of low voltage, fibrotic tissue appears to result in abnormal atrial activation, which may underlie

the initiation and maintenance of fibrillation 20. Indeed, both animal and human studies have

repeatedly shown that atrial fibrosis can lead to AF though mechanisms that cause alterations in

fibrillatory dynamics 40-42. By altering the LA substrate, fibrotic change and SRM probably aid in

the formation of circuits needed for reentry, thus perpetuating the atrial arrhythmia. As the

fibrotic process becomes more advanced, our data supports the notion that that the fibrillatory

circuits increase and become more extensive thereby making it increasingly difficult to restore

sinus rhythm. Interrupting the fibrillatory pathways in the early stages of fibrosis appears to be

important for success of ablation procedures as patients in the earliest remodeling stages (stages I

and II) showed higher success rates of 66.9% and 58.6% respectively.

The hallmark of SRM is atrial fibrosis, a factor leading to persistence of AF. However,

whether fibrosis is a cause or result of AF remains a subject of debate. Data here show

significant SRM changes on LGE-MRI in AF patients but not in control populations without AF.

In addition, the fibrosis stage correlates with AF clinical phenotype with more advanced

remodeling seen in persistent forms of AF. These findings support previous studies showing that

increasing AF burden leads to structural and functional remodeling 43. Progressive structural

changes in the atria are seen as paroxysmal AF eventually becomes persistent or permanent AF

nd human studiess hhhhaava

ms thaat ttt cacaususee llalalttteteraraaatitititioo

40 42 y

i

ocess becomes more advanced, our data supports the notion that that the fibrillato

crease and become more extensive thereby making it increasingly difficult to rest

hm Interr pting the fibrillator path a s in the earl stages of fibrosis appears t

dynynynynamamama iciciccsss 4044 -4242422.. By altering the LA substststrrar tte, fibrotic chah nggggee e and SRM probably

ioooon of circuits nneedddedded fororor reentttntryyy, thuus perrppetuuuatatattinininngg thhhe atriall arrrrhhyh thhhmmimm a. AAs thththe

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crease and dd bebb cococoome more extensiiive thhhherebbby yy makikikiinggg it iniini cccrc easisisingngngn lylylyl ddddifififi fifif cultltltlt tttto ooo rest

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DOI: 10.1161/CIRCEP.113.000689

13

and conversion to sinus rhythm can lead to reversal of these changes 44-46. These data support a

mechanism for atrial fibrosis that results from AF and the notion that AF begets AF 47.

On the other hand, atrial SRM can result from other disease processes such as valvular

heart disease (e.g. mitral stenosis) or heart failure48-50. In such cases, the fibrotic process appears

to precede the development of AF. In order to better understand the fundamental association

between fibrosis and AF, surveillance imaging of the LA in populations with and without AF

could help enhance our understanding of the fibrotic process and its consequences in

cardiovascular disease states. Our best understanding of the current available literature points to

more than one mechanism including accelerated LA fibrosis resulting from AF or alternatively

from fibrotic processes (e.g. structural disease) leading to AF.

Our study is limited as it is a single center, observational study. In addition, in order to

perform quality 3D LGE-MRI studies routinely in patients requires a high level of expertise in

MRI and support during the studies by expert MR imagers and technologists. Processing of the

MR images is laborious and requires experienced observers to perform the LA wall tracings and

to select the threshold levels. Improvements in image processing and automization of the

process is possible and is expected to simplify and help further standardize the image processing.

In addition, the operators performing the AF ablation procedures were not blinded to the results

of the MRI scan. Knowledge of the fibrosis score could have lead to biases in their approach to

the ablation procedure.

Non-invasive evaluation of myocardial tissue using LGE-MRI is a powerful tool for

detecting and quantifying atrial tissue disease and changes that result from the SRM process. In

patients with AF, the degree of LA wall SRM predicts response to catheter ablation therapy with

restoration of sinus rhythm highly unlikely in patients with advanced remodeling stage.

available literatureee ppppoo

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uality 3D LGE-MRI studies routinely in patients requires a high level of expertise

upport during the studies by expert MR imagers and technologists. Processing of

s is laborio s and req ires e perienced obser ers to perform the LA all tracing

tic prprprprocococo esesssseseses (e(e(e..g.. . structural disease) leaddddininii g to AF.

r sttuuudu y is limitteed aaas iiit isss aaa singngleee ccentterr, obsservvvatatatatioioioionnalll ssstudyy. Innnn addititittioioonn, in orororde

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DOI: 10.1161/CIRCEP.113.000689

14

Currently, the selection process for ablation procedures remains somewhat subjective with failed

anti-arrhythmic drug therapy, clinical phenotype, and patient treatment preferences all taken into

consideration. With better and more stringent selection criteria, we can improve outcomes and

cost effectiveness by avoiding ablation procedures unlikely to benefit patients with AF.

Conflict of Interest Disclosures: None

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by hhhheaeartrtt ffffaiaiiilulull rere iiiin n nn dddodo

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ov PG, Mitrofanova LB, Orshanskaya V, Ho SY. Structural abnormalities in atrias Ao

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ov PPPG,G,G,G MMMitititrororoofafafafanononon vavavava LLLLB,B,B,B OOOOrsrsrsr haaaansnsnsn kakakakayayyay VVV,,, HoHoHoo SSSSY.Y.YY SSStrtrtrtrucucucuctututuurararal l l l abababbnonononormrmrmmaalalititittieieiies s s s inininin aaaatriassociat dded witii h hhh prpp esence anddd ppper iisistencyyy off f attri llall ffffibibibriiilllll atatatatiion bubububutt nott withhthh aaaagegegege. J Aol. 2011;5558:88:8:222222225252525-2-22-22322 2.22.2.




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DOI: 10.1161/CIRCEP.113.000689

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Table 1. Comparison of baseline characteristics across structural remodeling stages in the AF group

Stage -I-

(n=133)

Stage -II-

(n=140)

Stage -III-

(n=71)

Stage -IV-

(n=42) P value

Age (yrs) 63±13 65±11 66±13 67±12 0.17

Female (%) 33.8 30.7 42.3 47.6 0.06

Hypertension (%) 62.9 61.4 57.8 66.7 0.81

Diabetes (%) 11.4 12.9 21.1 21.4 0.08

Coronary Disease (%) 13.6 12.5 24.4 14.3 0.10

Congestive Heart Failure (%) 6.1 13.0 12.7 7.1 0.41

LV ejection fraction (%) 58±12 59±10 57±12 56±13 0.16

CVA/TIA (%) 6.1 7.9 11.3 16.7 0.03

Paroxysmal AF (%) 61.7 46.4 49.3 26.2 0.002

Persistent AF (%) 38.4 53.6 50.7 73.8 0.002

Prior AAD use (%) 22.6 12.9 18.5 15.0 0.11

Atrial volume/BSA (ml/m2) 48±18 51±18 52±21 64±24 <0.0001

LA fibrosis (%) 6.7±2.0 15.2±2.9 23.3±2.8 40.9±10.4 <0.0001

7777 8.888

1 1

13131313.66 12122.5.5.5 24242424.4

666.6 1111 13131313.0.0.0. 12121212.7777

58585858±1±1±1±1222 59595959±±±1± 0000 5757577±1±1±1±12222

6.666 1111 7.777 9999 11111111.3333




DOI: 10.1161/CIRCEP.113.000689

21

Table 2. Comparison of baseline characteristics of AF patients and a non-AF control group

AF group

(n=386)

Non-AF group

(n=21) P value

Age (yrs) 64±12 54±17 0.01

Female (%) 36 38 0.47

Hypertension (%) 62.0 4.7 <0.0001

Diabetes (%) 15.2 19.0 0.64

Coronary Disease (%) 16.0 14.3 0.84

Congestive Heart Failure (%) 9.8 0 0.13

LV ejection fraction (%) 58±11 61±10 0.22

CVA/TIA (%) 8.8 0 0.16

Left atrial fibrosis (%) 16.6±11.2 3.5±2.3 <0.0001

Atrial volume/BSA (ml/m2) 51±20 31±10 <0.0001

<00.0.0000011

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nnn frfracacactitiononon ((%))%) 5858±1±111 6161±1±100 00.2222




DOI: 10.1161/CIRCEP.113.000689

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Table 3. Univariate and multivariate predictors of arrhythmia recurrence following catheter ablation: 1 year follow-up Univariate analysis Multivariate analysis

Hazard Ratio 95% CI P value Hazard Ratio 95% CI P value

Age (per 10 yr. increase) 1.22 1.05-1.43 0.011 1.12 0.94-1.34 0.192

Female 1.09 0.75-1.57 0.636 0.84 0.56-1.25 0.393

Hypertension 1.61 1.09-2.38 0.016 1.33 0.86-2.04 0.195

Diabetes 1.80 1.18-2.75 0.006 1.64 1.03-2.61 0.036

Coronary Disease 1.19 0.75-1.88 0.465 0.75 0.45-1.24 0.260

Congestive heart failure 1.19 0.68-2.07 0.543 1.17 0.65-2.09 0.607

Persistent AF 1.47 1.08-1.99 0.014 1.09 0.76-1.55 0.648

SRM Stage

Stage I Referent Referent

Stage II 1.47 0.91-2.38 0.116 1.29 0.81-1.82 0.303

Stage III 1.65 0.96-2.86 0.069 1.49 0.92-2.32 0.166

Stage IV 5.47 3.26-9.2 <0.0001 4.89 2.37-6.28 <0.0001

LA volume index (10 ml/m2) 1.16 1.07-1.26 <0.0001 1.05 0.96-1.17 0.279

0.84

1.33333

1 090 0141 08 1 99

0

9

9

7

0 1.18-2.75 0.00.006 111.1 64

9 0.75757575-11.8.8.8. 88 8 0.0.466665555 000.75757575

9 0.0.0.0.68686868-2-2-2- .0.0.0.077 77 0.0.0.0.545454543333 1.1.1.1.17171717

77 11 0808 11 9999 00 010144 11 0909




DOI: 10.1161/CIRCEP.113.000689

23

Figure Legends:

Figure 1. Segmentation process used for quantification of LA wall fibrosis. Panel A shows

single slice level from 3D late gadolinium enhancement data set pre-ablation. Panel B shows

endo and epi contours of the LA wall used for determining degree of fibrosis. Panel C shows

abnormal, fibrotic regions in green and normal, non-fibrotic tissue in blue. Panel D shows 3D

reconstruction of the entire data set separated to highlight the specific slice level in this example.

Figure 2. Four stages of LA structural remodeling (SRM) based on 3D late gadolinium

enhancement (LGE) MRI scans. Representative examples from patients in each stage of LA

remodeling in PA views (above examples of stages I-IV are 3%, 13%, 26%, and 56%,

respectively). Normal LA wall displayed in blue with SRM changes in green. The pulmonary

veins are shown in grey.

Figure 3. Kaplan-Meier rates of AF recurrence. Post AF ablation recurrences according to four

stages of atrial structural remodeling over 1-year follow-up period.

Figure 4. LA wall structural remodeling on LGE-MRI correlates with surgical biopsy

specimens. Examples from 3 surgical patients who underwent both 3D LGE-MRI scanning and

biopsy of the LA wall. “Control’ patient without AF shown left (1a-1c), AF patient with

moderate amount of SRM in center (2a-2c), and AF patient with advanced SRM on right (3a-3c).

3D LGE-MRI renderings show fibrosis/structural remodeling (SRM) in green with normal tissue

in blue (top panels). Masson’s trichrome stains collagen blue and LA myocytes red (middle

panels standard staining, bottom panels are subtraction images). Red box shows biopsy location.

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SUPPLEMENTAL MATERIAL Methods

Magnetic resonance imaging. Details for the 3D LGE-MRI imaging for left atrial

fibrosis at 1.5T and 3T are as follows: for the patient in sinus rhythm, data acquisition

was performed during LA diastole. Specifically, data acquisition window was 15% of

averaged cardiac cycle (aRR) and it was positioned from 65% to 80% of aRR (0%

corresponds to peak of R-wave). For AF patients with non-regular heart rate during the

imaging session, the duration of data acquisition window was reduced to 12% of aRR and

it was shifted closer to the R-wave and positioned from 47% to 59% of aRR. Other scan

parameters for LGE of LA at 3T scanner were: axial imaging volume,

FOV=400x400x110 mm, voxel size=1.25x1.25x2.5 mm, TR/TE=3.1/1.4 ms, flip angle of

14 degrees. Scan parameters for LGE of LA at 1.5T scanner were: axial image volume,

FOV=360x360x100 mm, voxel size=1.25x1.25x2.5 mm, TR/TE=5.2/2.4 ms, flip angle of

20 degrees. Typical scan time for LGE study was 6-12 minutes at 1.5 and 5-9 minutes 3T

scanner depending on patient respiration.

LGE-MRI assessment of left atrial structural remodeling. As noted in the manuscript,

quantification of LA remodeling was obtained using the methods previously described

with the addition of software implemented in Corview to improve determination of MRI

intensity values29. Some important details are as follows. After segmentation of the LA

wall (see methods in manuscript and Figure 1), next we estimate an intensity threshold

for enhancement (fibrosis) by inspection with an interactive intensity thresholding tool

within Corview. The thresholding tool displays the mean and standard deviations of the

MRI voxel values in the LA wall on top of a histogram of the wall intensity values. The

user then selects a threshold value for enhancement using a slider. As the threshold slider

is moved, the user can see which pixels are being selected in the both a 2D display of the

MRI image stack and a 3D volume rendering of the MRI. Typically, enhancement values

are found to be in the range of 2-4 standard deviations from the mean value. Once the

threshold has been determined, the percentage of enhancement is calculated as the

number of voxels in the LA wall segmentation with values above the threshold divided

by the total number of voxels in the LA wall segmentation.

Ablation procedure and follow up. The LA was accessed through two trans-septal

punctures under intracardiac echo guidance using a phased array catheter (Acunav,

Siemens Medical Solutions USA, Inc, Mountain View, CA). A 10-pole circular mapping

catheter (Lasso, Biosense Webster, Diamond Bar, CA) and a 3.5 mm Thermocool

ablation catheter (Biosense Webster, Diamond Bar, CA) were advanced into the LA for

mapping and ablation. A 14-pole catheter (TZ medical, Portland, OR; Biosense Webster,

Diamond Bar, CA) was used to record right atrial and coronary sinus electrograms and

was used as the reference catheter for 3D electro-anatomical mapping with CARTO

(Biosense Webster, Diamond Bar, CA). Radiofrequency energy was delivered with 50

Watts at a catheter tip temperature of 50 °C for 5 seconds, guided by electrogram

abolition recorded on the Lasso catheter. Ablation lesions were placed in a circular

fashion in the pulmonary vein antral region until electrical isolation of the pulmonary

veins was achieved. Additional lesions were placed along the LA posterior wall and

septum at the discretion of the operator.

Surgical biopsies and histochemical stains. Whole-field digital microscopy: Advanced

digital microscopy allowed examination of the entire heart tissue areas from the

epicardium to the endocardium. Whole-slide images were analyzed with the ScanScope

XT system equipped with the ImageScope 10.0 image analysis algorithms (Aperio

Technologies, Vista, CA) 31. Collagen content evaluation: we set the staining color

threshold of the ImageScope 10.0 Color deconvolution analysis algorithm to accurately

identify collagen based on its blue color. Subsequently, myocardial collagen content was

determined by running the algorithm on the stained myocardial tissue. “Interstitial

Fibrosis” was defined as the collagen content determined in the interstitial spaces and

endomysial/perimysial spaces including the collagen content around capillaries and small

vessels found within those spaces.

Tables.

Kaplan-‐meier rates of recurrence in paroxysmal AF patients. Percentages of paroxysmal AF patients in each stage are as follows: 61.7 Stage I, 46.4 Stage II, 49.3 Stage III, and 26.2 Stage IV.

0.00

0.25

0.50

0.75

1.00

0 500 1000analysis time

Stage I Stage IIStage III Stage IV

AF recurrence- Paroxysmal Patients

Kaplan-‐meier rates of recurrence in persistent AF patients. Percentages of persistent AF patients in each stage are as follows: 38.4 Stage I, 53.6 Stage II, 50.7 Stage III, and 73.8 Stage IV.

0.00

0.25

0.50

0.75

1.00

0 500 1000analysis time

Stage I Stage IIStage III Stage IV

AF Recurrence- Persistent Patients

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