Time Course of Inflammation, Myocardial Injury and...

DOI: 10.1161/CIRCEP.113.000876

1

Time Course of Inflammation, Myocardial Injury and Prothrombotic

Response Following Radiofrequency Catheter Ablation for Atrial Fibrillation

Running title: Lim et al.; Time Course of Inflammation Post AF Ablation

Han S. Lim, MBBS, PhD; Carlee Schultz, BHlthSci (Hons); Jerry Dang, MBBS; Muayad

Alasady, MBChB; Dennis H. Lau, MBBS, PhD; Anthony G. Brooks, PhD; Christopher X. Wong,

MBBS; Kurt C. Roberts-Thomson, MBBS, PhD; Glenn D. Young, MBBS; Matthew I. Worthley,

MBBS, PhD; Prashanthan Sanders, MBBS, PhD*; Scott R. Willoughby, PhD*

Centre for Heart Rhythm Disorders (CHRD), South Australian Health and Medical Research Institute (SAHMRI), University of Adelaide & Royal Adelaide Hospital, Adelaide, Australia.

*contributed equally as senior authors

Correspondence:

Prashanthan Sanders

Centre for Heart Rhythm Disorders

Department of Cardiology

Royal Adelaide Hospital

Adelaide, SA 5000

Australia

Tel: +61882222723

Fax: +61882222722

E-mail: [email protected]

Journal Subject Codes: [74] Other stroke treatment / medical, [188] Thrombosis risk factors, [22] Ablation/ICD/surgery

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DOI: 10.1161/CIRCEP.113.000876

2

Abstract:

Background - Inflammation has been linked to the genesis of stroke in atrial fibrillation (AF)

and is implicated in early recurrent arrhythmia after AF ablation. We aimed to define the time

course of inflammation, myocardial injury and prothrombotic markers following radiofrequency

(RF) ablation for AF and its relation to AF recurrence.

Methods and Results - Ninety consecutive AF patients (53% paroxysmal) undergoing RF

ablation were recruited. High-sensitivity CRP (hs-CRP), Troponin-T, creatine kinase-MB

(CKMB), fibrinogen and D-Dimer concentrations were measured at baseline, 1, 2, 3, 7-days and

1-month post-ablation. AF recurrence was documented at 3-days, 1, 3 and 6-months follow-up.

Troponin-T and CKMB peaked at day 1 post-procedure (both p<0.05). Hs-CRP peaked at day-3

post-procedure (p<0.05). Fibrinogen (p<0.05) and D-Dimer (p<0.05) concentrations were

significantly elevated at 1-week post-procedure. Ln hs-CRP elevation correlated with Ln

Troponin-T and fibrinogen elevation. The extent of Ln hs-CRP, Ln Troponin-T and fibrinogen

elevation predicted early AF recurrence within 3-days post-procedure (p<0.05 respectively), but

not at 3 and 6-months.

Conclusions - Patients undergoing RF ablation for AF exhibit an inflammatory response within

3-days. The extent of inflammatory response predicts early AF recurrence but not late recurrence.

Prothrombotic markers are elevated 1-week post-ablation and may contribute to increased risk of

early thrombotic events post AF ablation.

Key words: atrial fibrillation, catheter ablation, inflammation, myocardial inflammation, thrombosis

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DOI: 10.1161/CIRCEP.113.000876

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Introduction

Inflammation is increasingly recognized to play a significant role in the genesis and perpetuation

of atrial fibrillation (AF).1,2 Markers of inflammation such as C-reactive protein (CRP) are found

to be predictive of increased risk for future development of AF.2 Inflammation as a cause of AF

has also been suggested on the grounds of the time course of post-operative AF following

cardiac surgery, when the inflammatory cascade is most activated.1 Furthermore, patients with

AF undergoing catheter ablation are at increased risk of thromboembolic events, particularly in

the first 2-weeks after the procedure, although the exact mechanisms are not known.3

Radiofrequency (RF) ablation for atrial arrhythmias is known to cause an increase in

various markers of inflammation and myocardial injury.4,5 Moreover, biomarker detection of

myocardial injury is a key component in the third universal definition of myocardial infarction

and ablation is known to be a confounder.6 A protracted elevation of CRP is seen after AF

ablation, and following successful ablation of long-lasting persistent AF, a decline in CRP at 3-

months is observed.7,8 Studies linking inflammation levels at baseline and after ablation with

early and late AF recurrences following ablation have yielded varying results.4,7,9-11

To date, the specific time course of inflammation, myocardial injury and prothrombotic

markers following RF ablation for AF has not been well defined. We aimed to investigate the

inflammatory response post-ablation and its relation to AF recurrence and to examine the

relationship between inflammation and prothrombotic risk after ablation.

Methods

Patient Selection

Ninety consecutive patients undergoing elective RF catheter ablation for AF were prospectively

studied. All patients above the age of 18, with a history of AF were included. Exclusion criteria

are not known.3

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DOI: 10.1161/CIRCEP.113.000876

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were: prior myocardial infarction ( 3-months), unstable angina, surgery or ablation procedure

within the preceding 3-months, congenital heart disease, history of connective tissue disease or

chronic inflammatory condition, acute or chronic infection, chronic renal or liver failure. Type of

AF was defined according to the Heart Rhythm Society (HRS) expert consensus statement.12 All

patients provided written informed consent to the study protocol which was approved by the

Clinical Research Ethics Committee of the Royal Adelaide Hospital, Adelaide, Australia.

Patient Preparation

All patients underwent anticoagulation with warfarin to maintain their international normalized

ratio (INR) between 2-3 -weeks prior to the procedure. Warfarin was stopped 7-days prior

to the procedure and substituted with enoxaparin at a dose of 1- -

hours prior to the procedure. Transesophageal echocardiography was performed to exclude left

atrial thrombus. Transthoracic echocardiography was performed at baseline and post-procedure.

All antiarrhythmic agents, with the exception of amiodarone, were ceased 5-half-lives prior to

the procedure. Details of the ablation procedure are in the online-only Data Supplement.

Blood Collection

Blood samples were taken peripherally for total white cell count (WCC), neutrophil count, high-

sensitivity CRP (hs-CRP), Troponin-T, creatine kinase (CK), creatine kinase-MB (CKMB),

fibrinogen and D-Dimer measurements at the start of the procedure, and at 1, 2 and 3-days, 1-

week and 1-month post-procedure. Samples were analyzed immediately.

Markers of Inflammation, Myocardial Injury and Thrombosis

Hs-CRP was analyzed with an immunoturbimetric latex CRP assay (Olympus Diagnostics,

Melville, NY). Total WCC and neutrophil count was analyzed using the Sysmex XE2100

(Sysmex, Kobe, Japan). Cardiac troponin-T was analyzed with the Elecsys Troponin-T

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immunoassay (Roche Diagnostics, Indianapolis, IN). CK was analyzed using a kinetic UV serum

test (Olympus, Ireland). CKMB was analyzed with the Elecsys CKMB immunoassay (Roche

Diagnostics, Indianapolis, IN). Fibrinogen and D-Dimer were analyzed using the STAR

coagulation analyzer (Diagnostica Stago, Parsippany, NJ). Normal reference ranges were: WCC:

4.0-11.0 (x109/L), neutrophils: 1.8-7.5 (x109/L), hs-CRP: lower limit of detection (LLD) 0.08

mg/L, Troponin-T: 0-0.1 μg/L (LLD <150 U/L (LLD 3 U/L), CKMB: <7.0

μg/L (LLD 0. ), Fibrinogen: 1.5-4.0 g/L, D-Dimer: <0.5 FEU. The extent of biomarker

elevation was defined as the maximum recorded value (from day 1 to day 30) minus the baseline

value (day 0).

Patient Follow-up

Continuous monitoring was performed for 3-days following the procedure. Body temperature

was measured at baseline prior to the procedure and 6-hourly during the first 3 days post-

procedure. Outpatient follow ups were scheduled at 7-days, 1, 3, and 6-months post-procedure.

-month following ablation, a clinical review, ECG and 7-day Holter monitoring

was undertaken to determine the presence of recurrent arrhythmias. Recurrent arrhythmia was

defined as per the HRS expert consensus as any atrial arrhy -seconds. For the purposes

of this study, early recurrences -seconds within the first

3 days post-procedure while continuous monitoring was undertaken.

Warfarin was continued for a minimum of 3-months. In patients with a CHADS2 score

patients anticoagulation was continued for 12-months at which point its cessation was discussed

on an individual basis.

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Statistical Analysis

Continuous variables were expressed as mean±SD, and categorical data expressed as counts and

percentages. Data was tested for normality and log-transformed as appropriate. Continuous

variables between two groups were compared using Student t tests. Categorical variables were

compared using Fisher’s exact or Pearson’s chi-square tests as appropriate. Correlations between

the extents of elevation of the biomarkers were analyzed using Spearman’s correlation

coefficient. Linear mixed effects models were created to examine the temporal changes in

biochemical markers following AF ablation, in which time was included as a fixed effect and

where a compound symmetry correlation structure allowed for correlation within patients due to

repeated measurements. If the time main effect was significant, post-hoc testing was used to

reveal where the significant differences lied.

Univariate and multivariate linear regression analyses were used to determine the

predictors for the extent of elevation of each biomarker. All univariate predictors with p<0.10

were then added to a multivariate model. For outcomes that were log transformed, coefficient

estimates and confidence intervals were presented in the exponentiated form to describe the

effect of a one unit increase in the predictor on the geometric mean of the outcome. To predict

AF recurrence at 3 days, 1, 3 and 6 months from the extent of each biochemical marker elevation,

univariate logistic regression models were developed. Multivariate logistic regression models

were developed to identify predictors of early AF recurrence and AF recurrence at 6-months. P-

values <0.05 were considered statistically significant. Statistical analyses were performed using

PASW Statistics 18 (version 18.0.0).

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Results

Patient and Procedural Characteristics

Patient demographics and procedural characteristics are shown in table-1. These patients had

paroxysmal (44%), persistent (43%) and long-standing persistent AF (12%). Mean CHADS2

score was 0.9±0.9. The RF ablation times for PVI, CFAE ablation and linear ablation were

65.8±34.8, 32.3±21.6 and 20.6±16.0-minutes respectively. Total procedural time was

210.3±55.7-minutes.

Time Course of Inflammation, Myocardial Injury and Prothrombotic Markers

All measured markers increased significantly over time following RF ablation for AF (p<0.001

for all markers). Hs-CRP peaked at days 2-3 and was significantly elevated at 1-day to 1-week

post-RF ablation (Figure-1A). Total WCC and neutrophil count were significantly elevated days

1-3 post-procedure (Figures-1B and 1C).

Troponin-T peaked at day-1 post-procedure, and was significantly elevated up to day-3

post-procedure (Figure-2A). CKMB peaked similarly at day-1 post-procedure (Figure-2B). CK

levels were significantly elevated days 1-3 post-procedure (Figure-2C).

Prothrombotic markers seemed to peak slightly later at about 3-days and 1-week post-

procedure. Fibrinogen levels were significantly elevated at days 2-3 and 1-week post-procedure

(Figure-3A). D-Dimer levels were significantly elevated and peaked at 1-week post-procedure

(Figure-3B).

Correlation Between Inflammatory, Myocardial Injury and Prothrombotic Markers

The extent of Ln hs-CRP elevation correlated with the extent of Ln Troponin-T elevation

(rs=0.35, p<0.02), Ln CKMB elevation (rs=0.51, p<0.01) and fibrinogen elevation (rs=0.59,

p<0.01). There was a significant correlation seen between the extent of WCC elevation and

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neutrophil elevation (rs=0.93, p<0.01), but no significant correlation between these two markers

and Ln hs-CRP. The extent of Ln CKMB elevation correlated with the extent of Ln CK elevation

(rs=0.55, p<0.01).

Predictors of Elevation for Inflammatory, Myocardial Injury and Prothrombotic Markers

Univariate and multivariate linear regression analyses were used to determine the predictors of

the extent of elevation in each biomarker. Variables used were age, male gender, BMI (body

mass index), hypertension, diabetes mellitus, congestive heart failure, history of stroke/TIA

(transient ischemic attack), left atrial diameter, statin therapy, type of AF, baseline hs-CRP,

ablation approach, RF ablation time, total procedural time, fluoroscopy time and dose. Univariate

predictors of the extent of elevation of each specific biomarker, with p-values <0.10 were as

follows: hs-CRP elevation (mg/L): total procedural time (5 minute units) (coefficient=1.03, 95%

CI 1.01-1.06, p<0.01); Troponin-T elevation ( g/L): RF ablation time (5 minute units)

(coefficient=1.06, 95% CI 1.03-1.08, p<0.01), total procedural time (5 minute units)

(coefficient=1.02, 95% CI 1.00-1.04, p=0.02) and nonparoxysmal AF (coefficient=1.53, 95% CI

1.02-2.28, p=0.04); CK elevation (U/L): RF ablation time (5 minute units) (coefficient=1.05,

95% CI 1.00-1.11, p=0.06); and CKMB elevation ( g/L): RF ablation time (5 minute units)

(coefficient=1.05, 95% CI 1.00-1.10, p=0.06). A significantly higher Troponin-T elevation was

noted in persistent AF patients compared with paroxysmal AF (Ln Troponin-T 0.49 ± 0.55 vs.

0.06 ± 0.76, p=0.038). Multivariate analysis revealed RF ablation time as the only significant

multivariate predictor for Troponin-T elevation ( g/L) (RF ablation time, 5 minute units,

coefficient=1.04, 95% CI 1.01-1.08, p<0.05). There was no significant difference in baseline Ln

hs-CRP between patients with paroxysmal and persistent AF in this cohort (p=0.4) and baseline

Ln hs-CRP level was not a predictor of the extent of Ln hs-CRP elevation (p=0.2) or Ln

AF, baseline hs-CRCRRRPPPP

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Troponin-T elevation (p=0.7) post-ablation.

Follow-up and AF recurrence

Nineteen-patients (21.1%) had early atrial arrhythmia within 3-days. Twentytwo-patients had AF

recurrence between 4-30-days. Nine-patients had AF between 30-90-days. Forty-patients

sustained no AF. Fourteen had multiple AF recurrences during this period.

Patients with early AF recurrence post-procedure had a significantly higher elevation in

hs-CRP, Troponin-T, CKMB, fibrinogen levels and maximum body temperature compared with

patients without early AF recurrence (Figures 4A-F). Patients with AF recurrence at 1-month

also had a higher level of fibrinogen elevation (Figure-4E). The extent of Ln hs-CRP elevation

(OR 2.8 CI 1.3-6.0, p<0.01) and Ln Troponin-T elevation (OR 3.2 CI 1.1-9.7, p<0.05)

significantly predicted AF recurrence at 3-days, but not at 1, 3 and 6-months post-procedure. The

extent of fibrinogen elevation significantly predicted AF recurrences within 3-days (OR 3.6 CI

1.3-9.7, p=0.01) and 1 month (OR 2.5 CI 1.1-5.5, p<0.05). Maximum body temperature (°C)

during the first 3-days post-ablation was significantly associated with early AF recurrence (OR

11.1 CI 1.2-102.4, p=0.03).

At 6 months with a 3-month blanking period, 35 patients (39.8%) had AF recurrence. Of

these 35 patients, 30 patients also sustained recurrence during the 3-month blanking period.

There was a nonsignificant trend towards higher 6-month AF recurrence in patients with

persistent AF compared with paroxysmal AF (46% vs. 30%, p=0.1). Of interest, only about half

the patients who sustained initial AF recurrence within 3-days and 4-30 days post-ablation

(47.4% and 54.5% respectively) continued to sustain AF recurrence at 6-months , whereas all

the patients who had initial AF recurrence between 30-90 days continued to sustain recurrence at

6-months (p<0.001 between groups; Figure 5).

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Multivariate logistic regression models including age, type of AF, RF ablation time,

baseline Ln hs-CRP and extent of Ln hs-CRP elevation revealed extent of Ln hs-CRP elevation

(OR 2.9 CI 1.3-6.6, p=0.01) as the only significant predictor for early AF recurrence within 3

days. There were no significant interactions between the type of AF, RF ablation time and

baseline Ln hs-CRP with the extent of Ln hs-CRP elevation. However, multivariate logistic

regression models using the same variables did not reveal any significant predictors for AF

recurrence at 6-months.

One patient with a history of persistent AF, previous stroke and left ventricular

hypertrophy was diagnosed with a TIA 4-days post-procedure with complete neurological

recovery, 2-patients had groin complications and 2-patients had mild fluid overload requiring

diuretic therapy. Seven patients developed a small pericardial effusion on transthoracic

echocardiography performed 2-days post-procedure, which resolved on follow-up

echocardiography; however there was no significant difference in the extent of Ln hs-CRP

elevation in these patients.

Discussion

Main Findings

This study presents new information on the specific time course of inflammation, myocardial

injury and prothrombotic response following ablation for AF. The major findings were:

1. Patients undergoing RF catheter ablation for AF exhibited an inflammatory response and

myocardial injury within the first 3-days post-ablation.

2. The extent of inflammatory response predicts early recurrence of AF.

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3. Prothrombotic markers are elevated at 1-week post-AF ablation and correlates with the

inflammatory response. This may explain the increased risk of early thromboembolic

events post-ablation.

Inflammation and Myocardial Injury

Results of the current study demonstrate a consistent inflammatory response post-RF ablation for

AF within the first 3-days post-ablation. In the current study markers of myocardial injury were

elevated early (1-day) after RF ablation. The pattern of elevation for these markers was

consistently earlier compared to the inflammatory markers (peak 3-days). Other studies on mixed

cohorts of patients undergoing RF ablation have found a peak in markers of myocardial injury

within the first few hours post-ablation.5,13 The findings of RF ablation time being an

independent predictor of Troponin-T elevation, consistent with previous studies,5,13 and higher

extent of Troponin-T elevation in persistent AF patients suggest that markers for myocardial

injury relate to the extent of ablation, with more extensive ablation performed in patients with

persistent forms of AF.

Our study demonstrated a correlation between markers of myocardial injury and hs-CRP

elevation post-ablation. This is in accordance with the cardiac surgical setting, where a

significant correlation was shown between post-operative troponin-I levels and clinical

inflammation associated parameters.14 With the positive correlation between hs-CRP elevation

and markers of myocardial injury, this inflammatory response could partly be explained by local

myocardial injury. However, the elevation in peripheral WCC, neutrophil count, hs-CRP,

prothrombotic markers and body temperature suggest a systemic inflammatory process in

addition to local inflammation post-RF ablation.

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12

Inflammation and Thrombotic Risk

Inflammation and thrombogenesis in AF are increasingly identified as being intimately

linked.12,15-19 CRP levels are positively correlated with clinical risk factors of stroke.18 We have

previously reported increased thrombogenesis and inflammatory mediators within the human

atrium with the onset of AF.19 Furthermore, D-dimer levels have been shown to predict

thromboembolic events even in anticoagulated AF patients.20

Results of the current study document an elevation in the prothrombotic markers

fibrinogen (Figure-3A) and D-dimer (Figure-3B). Fibrinogen elevation positively correlated with

hs-CRP elevation. The peak elevation of these markers occurred at 7-days post-ablation

compared to the inflammatory responses (1-3 days) and myocardial injury (1-day). This delayed

prothrombotic timeframe coincides with the finding that the majority of thromboembolic

complications following AF ablation occur within the first 2-weeks post-procedure.3 These

findings suggest that inflammation could be an important contributing factor to the increased

prothrombotic state in AF early post-ablation.

Inflammation and AF Recurrence

Previous studies have shown that baseline pre-procedural hs-CRP levels were independently

predictive of AF recurrence following RF ablation for AF.11 In this study, we did not find a

significant relationship between the baseline inflammatory state and the extent of elevation in the

markers of inflammation and myocardial injury, and AF recurrence at 6 months. However, our

study found that the degree of inflammatory response post-ablation (extent of hs-CRP elevation)

was significantly associated with early AF recurrence within 3-days post procedure. This finding

is consistent with Koyama et al. who found that acute inflammatory changes after ablation may

be responsible for immediate AF recurrence.9

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The impact of early AF recurrence on long term outcome remains debatable. In a study

by Richter et al. AF recurrence within 48-hours of ablation was a predictor of poorer clinical

outcome on follow-up.10 However, in another study, the patient cohort that experienced

immediate AF recurrence within 3 days subsequently had a higher AF-free rate at 6 months

compared with those with later recurrences between 4 and 30 days.9 In our study, we found that

about half of the patients with initial early AF recurrence continued to have AF recurrence at 6-

months, whereas all patients with recurrence in the 30-day to 3-month period continued to have

recurrence at 6-months. Our results suggest that in about half of the early AF recurrences, the

effect is transient and may not have a negative impact on long-term outcome, whereas

recurrences between 30 days to 3 months may be due to a different pathophysiology, such as

pulmonary vein reconnection and confers poorer long-term outcome.9

Several studies have found that ameliorating the post-ablation inflammatory response by

steroids and anti-inflammatories reduces the incidence of early arrhythmic recurrences.21,22

Colchicine administered for 3-months was found to decrease early AF recurrences after AF

ablation.22 Transient administration of steroids for 3-days after ablation not only reduced

immediate AF recurrence but also AF recurrence at mid-term follow-up.21 However, in an

experimental porcine study, the use of prophylactic steroids in pigs which underwent atrial

ablation was not shown to alter the systemic inflammatory response or the healing of the

lesions.23

Clinical Implications

This study demonstrated a consistent increased inflammatory response exhibited within 3 days

post-RF ablation for AF. The extent of inflammatory response was associated with early AF

recurrence. There is emerging evidence that early AF recurrence has a different underlying

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14

mechanism, but may still influence long-term recurrence. Understanding the time course of

inflammation could help direct the timing and regimen of future potential interventions aimed at

ameliorating the inflammatory response post-AF ablation.21,22

In our study, increased prothrombotic tendency was documented at about one week post-

AF ablation. This may explain the increased thromboembolic rates within the first 2-weeks post

catheter ablation for AF.3 Strategic antithrombotic measures targeting this specific time frame

may further decrease post-procedural thromboembolic events.

Study Limitations

The lack of further significant predictors for the elevation in the various inflammatory,

myocardial injury and prothrombotic markers in our study could be due to limited numbers in the

study. Alternatively, this could be due to the mechanism of the documented inflammatory

response being multifactorial. Secondly, the earliest blood sample measurement made following

ablation was at post-procedural day-1, which may have missed the exact peak for myocardial

injury.

Conclusion

Patients undergoing catheter ablation for AF exhibit an inflammatory response and myocardial

injury within the first few days post ablation. The extent of inflammatory response predicts early

AF recurrence but not late recurrence. Prothrombotic markers are elevated one week post

catheter ablation, associated with inflammation and may contribute to the increased risk of early

thrombotic events post AF ablation.

Funding Sources: This study was supported by a Grant-in-Aid from the National Heart

Foundation of Australia. Drs. Lim and Alasady are supported by Postgraduate Research

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15

Scholarships from the National Health and Medical Research Council of Australia (NHMRC)

and Earl Bakken Electrophysiology Scholarships from the University of Adelaide. Dr.

Willoughby is supported by a Career Development Fellowship by the NHMRC. Dr Lau is

supported by Postdoctoral Fellowships from the NHMRC. Drs. Brooks and Sanders are

supported by the National Heart Foundation of Australia. Dr Sanders is supported by a

Practitioner Fellowship from the NHMRC.

Conflict of Interest Disclosures: Dr Sanders reports having served on the advisory board of

Medtronic, St Jude Medical, Sanofi-Aventis and Merck, Sharpe and Dohme. Dr Sanders reports

having received lecture fees and research funding from Biosense-Webster, Medtronic, Boston

Scientific, Biotronik and St Jude Medical.

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3. Oral H, Chugh A, Ozaydin M, Good E, Fortino J, Sankaran S, Reich S, Igic P, Elmouchi D, Tschopp D, Wimmer A, Dey S, Crawford T, Pelosi F, Jr., Jongnarangsin K, Bogun F, Morady F. Risk of thromboembolic events after percutaneous left atrial radiofrequency ablation of atrial fibrillation. Circulation. 2006;114:759-765.

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5. Katritsis D, Hossein-Nia M, Anastasakis A, Poloniecki I, Holt DW, Camm AJ, Ward DE, Rowland E. Use of troponin-t concentration and kinase isoforms for quantitation of myocardial injury induced by radiofrequency catheter ablation. Eur Heart J. 1997;18:1007-1013.

6. Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD. Third universal definition of myocardial infarction. J Am Coll Cardiol. 2012;60:1581-1598.

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T, DDDDokainish HH, Lakkkkkkis NNNNMM. RRRRolle of iinnnflammm atatatioioionnn n iin iiinnnitiattioon annd peeeerprppeetuuatiiionnn latatatioooon: A sysysyystemematiciic revvvieeew ww ofoffof thehehe pububublishheed ddddaata a.... JJ Ammmm Coolll CaCaCaCarrdrr iollll. 20202 007;5550:20

RJ, MaMMM rtin DDDOOO, AAAApppppperson-HaHHH nsen CCC, HHoH uggghhth alinii g gg PLPLPL, RaRaRaRautahahahharjujujuj PPPP, KrKK onnnnmamamamalll l RAVan Wagogogogonenenener rr DRDRDRDR,,,, PsPsPsatatata y yyy BMBMBMM, , , , LaLaLaLaueueueu r r r r MSMSMSMS,,, ChChChChununung g g g MKMKMMK... InnInInflflflflamamamammamamamatitititiononon aaaas s ss a risk facbb irillll tatiio CiCi ll tii 20200303 1;10808 3:3000066 30301010


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10. Richter B, Gwechenberger M, Socas A, Marx M, Gossinger HD. Frequency of recurrence of atrial fibrillation within 48 hours after ablation and its impact on long-term outcome. Am J Cardiol. 2008;101:843-847.

11. Lin YJ, Tsao HM, Chang SL, Lo LW, Tuan TC, Hu YF, Udyavar AR, Tsai WC, Chang CJ, Tai CT, Lee PC, Suenari K, Huang SY, Nguyen HT, Chen SA. Prognostic implications of the high-sensitive c-reactive protein in the catheter ablation of atrial fibrillation. Am J Cardiol.2010;105:495-501.

12. Willoughby SR, Roberts-Thomson RL, Lim HS, Schultz C, Prabhu A, De Sciscio P, Wong CX, Worthley MI, Sanders P. Atrial platelet reactivity in patients with atrial fibrillation. Heart Rhythm. 2010;7:1178-1183.

13. Madrid AH, del Rey JM, Rubi J, Ortega J, Gonzalez Rebollo JM, Seara JG, Ripoll E, Moro C. Biochemical markers and cardiac troponin i release after radiofrequency catheter ablation: Approach to size of necrosis. Am Heart J. 1998;136:948-955.

14. Knayzer B, Abramov D, Natalia B, Tovbin D, Ganiel A, Katz A. Atrial fibrillation and plasma troponin i elevation after cardiac surgery: Relation to inflammation-associated parameters. J Card Surg. 2007;22:117-123.

15. Conway DS, Buggins P, Hughes E, Lip GY. Relationship of interleukin-6 and c-reactive protein to the prothrombotic state in chronic atrial fibrillation. J Am Coll Cardiol. 2004;43:2075-2082.

16. Sanders P, Morton JB, Kistler PM, Vohra JK, Kalman JM, Sparks PB. Reversal of atrial mechanical dysfunction after cardioversion of atrial fibrillation: Implications for the mechanisms of tachycardia-mediated atrial cardiomyopathy. Circulation. 2003;108:1976-1984.

17. Nakamura Y, Nakamura K, Fukushima-Kusano K, Ohta K, Matsubara H, Hamuro T, Yutani C, Ohe T. Tissue factor expression in atrial endothelia associated with nonvalvular atrial fibrillation: Possible involvement in intracardiac thrombogenesis. Thromb Res. 2003;111:137-142.

18. Thambidorai SK, Parakh K, Martin DO, Shah TK, Wazni O, Jasper SE, Van Wagoner DR,

ARARARAR, , TsTsTsTsaiaiaiai WWWWC,C,C,C, CCCChahahahangngggostic c imimii plllplicicii atatttioiiionsns ooooffff ttlationnnn AmAmAmAm JJJJ CCCCarararardidididioool

4

g SR, Roberts-Thomson RL, Lim HS, Schultz C, Prabhu A, De Sciscio P, Wh e0

d AH, del Rey JM, Rubi J, Ortega J, Gonzalez Rebollo JM, Seara JG, Ripoll E, M

to si e of necrosis A H t J 1998;136:948 955J

495555-5-5-5-5010100 .

ggghg bbbyb SR, Robberrts-T-T-Thhhomsmsmson RRRRL,,, LLimm HHHS,, SSchhhhululultztztztz CC, PrPrPrabhuhu AAAA, DDe SSSScicicisccio PPP, WWWhleyeyey MMMI, Sanananandeers P. AAtriiialalal ppplaateteteteleeet reacacactiviityy innnn ppapatttit eenttts withh aatririririalalalal fibbbbriririllaatiion. HHHe010;7777:1:1:1171771788-8 1111111 8383833.

d AH,HHH ddd lell RRReyeyey JJJJM,MMM RRR bbubii i JJJ, OOOOrteggga JJJ, GGGGonzallel z ReRRR bbbob llllo JMJMJMJM, SeSeSeeara JGJGJGG, RiRiRiRipopopopolllllll EEEE, Mal markerrrrsss ananannd d d cacacacardrdrdrdiai cccc trtrtrropoppponononninininin iiii rrrreleleleleaeaeaeaseseee aaaaftftftftererer rrradadadadioioioiofrfrfreqeqeqequeueueuencncncncy y y y cacacc ththththeteeterererer aaaablation: tt isi ff iis AA HH t JJ 19199898 1;13636 9:94848 995555JJ


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Chung MK, Murray RD, Klein AL. Relation of c-reactive protein correlates with risk of thromboembolism in patients with atrial fibrillation. Am J Cardiol. 2004;94:805-807.

19. Lim HS, Willoughby SR, Schultz C, Gan C, Alasady M, Lau DH, Leong DP, Brooks AG, Young GD, Kistler PM, Kalman JM, Worthley MI, Sanders P. Effect of atrial fibrillation on atrial thrombogenesis in humans: Impact of rate and rhythm. J Am Coll Cardiol. 2013;61:852-860.

20. Vene N, Mavri A, Kosmelj K, Stegnar M. High d-dimer levels predict cardiovascular events in patients with chronic atrial fibrillation during oral anticoagulant therapy. Thromb Haemost.2003;90:1163-1172.

21. Koyama T, Tada H, Sekiguchi Y, Arimoto T, Yamasaki H, Kuroki K, Machino T, Tajiri K, Zhu XD, Kanemoto-Igarashi M, Sugiyasu A, Kuga K, Nakata Y, Aonuma K. Prevention of atrial fibrillation recurrence with corticosteroids after radiofrequency catheter ablation: A randomized controlled trial. J Am Coll Cardiol. 2010;56:1463-1472.

22. Deftereos S, Giannopoulos G, Kossyvakis C, Efremidis M, Panagopoulou V, Kaoukis A, Raisakis K, Bouras G, Angelidis C, Theodorakis A, Driva M, Doudoumis K, Pyrgakis V, Stefanadis C. Colchicine for prevention of early atrial fibrillation recurrence after pulmonary vein isolation: A randomized controlled study. J Am Coll Cardiol. 2012;60:1790-1796.

23. Nascimento T, Mota F, dos Santos LF, de Araujo S, Okada M, Franco M, de Paola A, Fenelon G. Impact of prophylactic corticosteroids on systemic inflammation after extensive atrial ablation in pigs. Europace. 2012;14:138-145.

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Table 1. Baseline Clinical, Echocardiographic and Procedural Characteristics of AF Cohort

Characteristics Patient cohort (n=90)

Age (years) 64.2 ± 16.5

Male gender 58 (64%)

BMI (kg/m2)

<18.5 (1%)

18.5-24.9 (14%)

25.0-29.9 (49%)

(36%)

Mean BMI (kg/m2) 29.4 ± 4.7

Comorbidities

Congestive heart failure 4 (4%)

Hypertension 47 (52%)

Diabetes mellitus 8 (9%)

Dyslipidaemia 29 (32%)

Current or ex-smoker 25 (28%)

Coronary artery disease 8 (9%)

Valvular disease 2 (2%)

Obstructive sleep apnoea 22 (24%)

Previous stroke/TIA

CHADS2 score

0

1

2

Mean CHADS2 score

10 (11%)

36 (40%)

36 (40%)

12 (13%)

6 (7%)

0.9 ± 0.9

Type of AF

Paroxysmal AF 40 (44%)

Persistent AF 39 (43%)

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Long-standing persistent AF 11 (12%)

Proportion of Lone AF 34 (38%)

Usual Medications

No. of AAD 0.8 ± 0.4

Amiodarone 7 (8%)

Sotalol 23 (26%)

Flecainide 34 (38%)

Statin therapy 31 (34%)

ACE-inhibitor or ARB 60 (67%)

Echocardiographic parameters

LA diameter, parasternal view (mm) 40.0 ± 6.0

LA size (cm2) 23.2 ± 4.0

RA size (cm2) 20.6 ± 4.8

LVEF (%) 58.0 ± 10.4

Procedural details

PVI only 21 (23%)

PVI and linear ablation 26 (29%)

PVI, linear ablation and CFAE ablation 43 (48%)

RF ablation time (min) 101.7 ± 31.8

Total procedural time (min) 210.3 ± 55.7

Data are mean ± SD or n (%) unless otherwise stated. BMI = body mass index; TIA = transient ischemic attack; CHADS2 = congestive heart failure,

PVI = pulmonary vein isolation; AAD = antiarrhythmic drugs; CFAE = complex fractionated atrial electrograms; ACE = angiotensin converting enzyme; ARB = angiotensin receptor blocker.

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Figure Legends:

Figure 1. Time Course of Inflammatory Markers Following RF Ablation for AF. (A) Hs-CRP.

*p<0.05 (compared to baseline); p<0.001 (change over time). NB: Descriptive plot shown.

Statistical analyses performed using mixed effects models on logged values, in which statistical

significance was achieved (same applies to subsequent figures on Troponin-T, CKMB, CK and

D-dimer). (B) WCC. *p<0.05 (compared to baseline); p<0.001 (change over time). (C)

Neutrophil Count. *p<0.05 (compared to baseline); p<0.001 (change over time).

Figure 2. Time Course of Markers of Myocardial Injury Following RF Ablation for AF. (A)

Troponin-T. *p<0.05 (compared to baseline); p<0.001 (change over time). (B) CKMB. *p<0.05

(compared to baseline); p<0.001 (change over time). (C) CK. *p<0.05 (compared to baseline);

p<0.001 (change over time).

Figure 3. Time Course of Prothombotic Markers Following RF Ablation for AF. (A) Fibrinogen.

*p<0.05 (compared to baseline); p<0.001 (change over time). (B) D-dimer. *p<0.05 (compared

to baseline); p<0.001 (change over time).

Figure 4. Extent of Elevation in Biomarkers and Early AF Recurrence. (A) Hs-CRP. p<0.01 AF

recurrence vs. no recurrence. (B) Troponin-T. p<0.05 AF recurrence vs. no recurrence. (C)

CKMB. p=0.01 AF recurrence vs. no recurrence. (D) Fibrinogen and Early AF Recurrence

within 3-days. p<0.01 AF recurrence vs. no recurrence. (E) Fibrinogen and AF Recurrence at 1-

over time)).

T A

T <

n

h

Timemememe CCCouououursrsrse ofofoff Markers of Myocardial InInInjjjjuuury Followinng RFRFRFRF Ablation for AF. (A

T. ***p<0.05 (comompaaareed tooo bbaselelellinnne)); p<00.00011 (cccchahahangnngn e ovovover timime)))). (B) CKCKCKC MBM . *ppp<

to bbbasaasaselelelinininine)); <<p<0.000 00000000111 (chahahahanngnge ovvererere tttimimime)e)). (C(C(C(C)))) CKCKCKCK. ***p* <0<0<0<0.0000555 (((c( ommmmpapapapared d ttto bbbbas lllelin

hanggge over timimimme)e)e)).


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DOI: 10.1161/CIRCEP.113.000876

21

month. p<0.01 AF recurrence vs. no recurrence. (F) Body Temperature and AF Recurrence

within 3-days. p=0.01 AF recurrence vs. no recurrence.

Figure 5. Prevalence of AF Recurrence at 6-months According to Time of Initial AF Recurrence.

p<0.001 between groups. p=0.01 between the initial 3-days recurrence group vs. 30-90-days

recurrence group; p=0.03 between the initial 4-30-days recurrence group vs. 30-90-days

recurrence group; p=0.8 between the initial 3-days recurrence group vs. 4-30-days recurrence

group; p<0.01 respectively between the no recurrence group and initial 3-days, 4-30-days and

30-90-days recurrence groups.

al 3-daysy , 4-30-daaysysysys a


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Prashanthan Sanders and Scott R. WilloughbyChristopher X. Wong, Kurt C. Roberts-Thomson, Glenn D. Young, Matthew I. Worthley,

Han S. Lim, Carlee Schultz, Jerry Dang, Muayad Alasady, Dennis H. Lau, Anthony G. Brooks,Radiofrequency Catheter Ablation for Atrial Fibrillation

Time Course of Inflammation, Myocardial Injury and Prothrombotic Response Following

Print ISSN: 1941-3149. Online ISSN: 1941-3084 Copyright © 2014 American Heart Association, Inc. All rights reserved.

Dallas, TX 75231is published by the American Heart Association, 7272 Greenville Avenue,Circulation: Arrhythmia and Electrophysiology

published online January 20, 2014;Circ Arrhythm Electrophysiol.

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SUPPLEMENTAL MATERIAL

Ablation Procedure

Electrophysiological study and ablation was performed with sedation utilizing midazolam

and fentanyl. The left atrium (LA) was accessed using a single transeptal puncture. All

patients underwent wide encircling pulmonary vein ablation with an end point of isolation

confirmed by circumferential mapping (PVI; Lasso, Biosense-Webster, Diamond Bar,

California) with either elimination or dissociation of pulmonary venous potentials. Ablation

of the pulmonary veins was performed using a 3.5mm-tip externally irrigated catheter

(Thermocool, Biosense-Webster) delivering 25-30W of power with irrigation rates of 17-

30ml/min. Additional substrate modification (linear ablation along the LA roof and/or mitral

isthmus and/or ablation of complex fractionated atrial electrograms (CFAE)) was performed

in patients with an episode of AF ≥48hours, evidence of structural heart disease or with the

largest atrial diameter ≥57mm. Linear ablation and CFAE ablation was performed with a

delivered power of 25-35W with irrigation rates of 30-60-ml/min.

After LA access was achieved, repeated bolus unfractionated heparin was utilized to

maintain the activated clotting time between 300-350s. After ablation, sheaths were removed

without reversal of heparin and warfarin commenced the night of the procedure. Patients

were administered enoxaparin 0.5mg/kg twice a day until the INR≥2.

Supplementary Table 1: Inflammatory, myocardial injury and prothrombotic markers following RF ablation for AF

Baseline

Day 1

Day 2

Day 3

Day 7

Day 30

Hs-CRP (mg/L)

2.57 ± 2.16

12.14 ± 12.09*

36.89 ± 34.87*

44.29 ± 37.37*

11.65 ± 16.39*

1.29 ± 0.81

WCC (x109/L)

6.14 ± 1.98

8.91 ± 2.37*

7.37 ± 2.18*

7.42 ± 2.11*

7.01 ± 2.14*

6.71 ± 1.85

Neutrophil (x109/L)

3.95 ± 1.76

6.78 ± 2.10*

5.13 ± 1.85*

5.14 ± 1.82*

4.66 ± 1.70

3.97 ± 1.20

Troponin-T (µg/L)

0.05 ± 0.08

1.61 ± 1.07*

1.01 ± 0.75*

0.54 ± 0.46*

0.11 ± 0.13

0.07 ± 0.19

CK (U/L)

101.25 ± 53.91

216.31 ± 141.03*

182.59 ± 190.57*

207.25 ± 275.46*

105.75 ± 60.55

72.33 ± 30.83

CKMB (µg/L)

3.21 ± 1.20

10.65 ± 5.10*

4.95 ± 2.27*

3.54 ± 1.10

2.66 ± 0.72

2.27 ± 0.29

Fibrinogen (g/L)

3.11 ± 0.61

3.21 ± 0.55

4.12 ± 0.76*

4.71 ± 0.86*

4.71 ± 1.42*

3.10 ± 0.75

D-Dimer (FEU)

0.28 ± 0.13

0.32 ± 0.24

0.32 ± 0.29

0.44 ± 0.30*

0.58 ± 0.46*

0.41 ± 0.24*

Data presented as mean ± SD. All markers demonstrated a significant increase over time (p<0.001). *p<0.05 compared to baseline values. Note:

Statistical analyses performed using mixed effects models on logged data as appropriate, in which statistical significance was achieved.

Supplementary Table 2: Extent of elevation in biomarkers and early AF recurrence

AF recurrence

No AF recurrence

p-value

Ln Hs-CRP elevation (mg/L)

3.75 ± 0.80

2.79 ± 1.07

<0.005

Ln Troponin-T elevation (µg/L)

0.59 ± 0.62

0.07 ± 0.77

<0.05

Ln CKMB elevation (µg/L)

2.35 ± 0.57

1.38 ± 0.95

0.01

Fibrinogen elevation (g/L)

2.23 ± 1.39

1.14 ± 0.70

<0.005

Fibrinogen elevation (g/L)

(recurrence at 1-month)

1.96 ± 1.25

1.13 ± 0.63

0.005

Body temperature (°C)

37.6 ± 0.6

37.2 ± 0.3

0.011

Data presented as mean ± SD.

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