diffuse ventricular fibrosis is a la te outcome of...

DOI: 10.1161/CIRCEP.113.000515

1

Diffuse Ventricular Fibrosis is a Late Outcome of Tachycardia-Mediated

Cardiomyopathy Following Successful Ablation

Running title: Ling et al.; Diffuse Ventricular Fibrosis Post-TMC

Liang-han Ling, MBBS1,2; Jonathan Kalman, MBBS, PhD2; Andris Ellims, MBBS1; Leah Iles,

MBBS1; Caroline Medi, MBBS, PhD1,2; Craig Sherratt, BAppSc1; David Kaye, MBBS, PhD1,2;

James Hare, MBBS, PhD1; Peter Kistler, MBBS, PhD1; Andrew Taylor MBBS PhD1

1Alfred Hospital and Baker IDI Heart and Diabetes Institute; 2Royal Melbourne Hospital and

Faculty of Medicine, Dentistry, and Health Sciences, University of Melbourne, Australia

Correspondence:

Prof Jonathan Kalman

Royal Melbourne Hospital

Victoria, 3050

Australia

Tel: +61 3 9349 5400

Fax: +61 3 9349 5411

E-mail: [email protected]

Journal Subject Codes: [5] Arrhythmias, clinical electrophysiology, drugs, [104] Structure, [105] Contractile function, [30] CT and MRI

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DOI: 10.1161/CIRCEP.113.000515

2

Abstract

Background - Successful arrhythmia ablation normalizes ejection fraction (EF) in tachycardia-

mediated cardiomyopathy (TMC), but recurrent heart failure and late sudden death have been

reported. The aim of this study was to characterize the left ventricle (LV) of TMC patients long

after definitive arrhythmia cure.

Methods and Results - Thirty-three patients with a history of successfully ablated incessant focal

atrial tachycardia 64±36 months prior, and 20 healthy controls were recruited. At ablation, 18

patients had EF<50% (AT-Low EF) that recovered within 3 months from 37±12 to 56±4%

(p<0.001), while 15 patients had EF>55% (AT-Normal EF). No subjects had EF of 50% to 55%.

Subjects underwent echocardiography with speckle tracking and contrast-enhanced cardiac

magnetic resonance imaging (CMR) with ventricular T1 mapping as an index of diffuse fibrosis.

CMR was performed using a clinical 1.5-T scanner and 0.2 mmol/kg gadolinium-DTPA for

contrast. Subject characteristics were similar across the 3 groups. Compared to AT-Normal EF

patients and controls, AT-Low EF patients had lower EF (60±6 vs 64±4 and 65±4%, p<0.05),

greater indexed LV end-diastolic volume (102±34 vs 84±14 and 85±16 ml/m2, p<0.05), and

greater indexed LV end-systolic volume (41±11 vs 31±7 and 30±8 ml/m2, p<0.01) on CMR.

Compared to controls, AT-Low EF patients had reduced global LV corrected T1 time (442±53 vs

529±61, p<0.05) consistent with diffuse fibrosis.

Conclusions - TMC patients exhibit differences in LV structure and function including diffuse

fibrosis long after arrhythmia cure, indicating that recovery is incomplete.

Key words: tachyarrhythmia, ablation, magnetic resonance imaging, T1 mapping, cardiomyopathy

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Introduction

Tachycardia-mediated cardiomyopathy (TMC) is an important cause of reversible left ventricular

(LV) systolic dysfunction and may complicate supraventricular tachyarrhythmias.1, 2 Key

features include reduced global contractility, extracellular matrix remodeling, and LV chamber

dilatation. Severity of systolic impairment in TMC shows dependence on tachycardia rate and

duration.3-5 Successful rate or rhythm control results in normalization of ejection fraction (EF)

within weeks to months in the absence of concurrent causes of cardiomyopathy.1, 6-8

Despite good early outcomes, rapid deterioration of systolic function with tachycardia

recurrence and late sudden death have been reported, raising the possibility that LV myocardial

substrate remains diseased despite normalization of overall systolic function.8, 9 Large animal

models of tachypacing-induced heart failure show EF recovery following cessation of

tachypacing, but also reveal persistent LV dilatation accompanied by diffuse interstitial fibrosis,

reduced contractility, and impaired relaxation during the immediate recovery phase.10-13

Furthermore, a series of 24 TMC patients treated successfully for a variety of arrhythmias

demonstrated persistent LV dilatation up to 14 months following normalization of EF.6

Longer-term follow-up studies of TMC that characterize LV structure and function are

lacking, despite increasing availability of powerful imaging modalities such as cardiac magnetic

resonance (CMR). The long-term impact of incessant inappropriate tachycardia in subjects who

do not develop gross LV systolic dysfunction is unknown. In this study, we performed detailed

non-invasive assessment of LV function, morphology, and fibrosis, as well as clinical outcomes

in a cohort of patients with and without TMC in the setting of incessant focal atrial tachycardia at

a mean of 5 years following successful arrhythmia ablation.

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Methods

Study Population

The study was performed at the Royal Melbourne Hospital and the Alfred Hospital in

Melbourne, Australia, and had Human Research Ethics Committee approval. Consenting patients

with a history of incessant focal atrial tachycardia (AT) and successful ablation between January

1997 and December 2011 were recruited. Patients with pre-existing LV dysfunction were

excluded. Patients were considered to have pre-existing LV dysfunction when cardiomyopathy

occurred in the context of known significant coronary artery disease, valvular heart disease,

congenital heart disease, or inherited cardiomyopathy; cardiomyopathy had been documented

before the onset of tachycardia; or the echocardiographic abnormalities were segmental or of a

pattern attributable to another cause. At the time of their ablation procedure, 18 patients had an

EF (AT-Low EF) while 15 patients an EF of 55% (AT-Normal EF), as determined by

Simpson’s biplane method on clinical echocardiography. No patients had an EF of 50% to 55%.

All 33 patients had incessant AT where tachycardia was defined by the presence of 10

consecutive tachycardia beats on 12-lead electrocardiogram or Holter monitor and incessant

tachycardia was defined as continuous tachycardia or continuous paroxysms of tachycardia

separated by 2 sinus beats.14 Following successful ablation, EF of all AT-Low EF patients (as

determined on clinical echocardiography) either recovered to >55% or made an absolute

improvement of at least 10% within 3 months, resulting in a clinical diagnosis of TMC. Success

of ablation was based on absence of recurrence on symptoms and repeated electrocardiographic

evaluation at 1, 3, 6 and 12 month follow-up visits and annually thereafter. Holter monitoring

was performed at 3, 6 and 12 month visits and thereafter if patients described symptoms. ACE-

inhibitor and -blocker therapy was not routinely prescribed following catheter ablation. A

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control group comprising healthy volunteers having a similar age and gender distribution to the

AT patients was recruited fmor the general public through advertising within our institutions. All

subjects underwent clinical assessment, CMR, echocardiography, and the SF-36 Health Survey

as an assessment of quality of life.15 All prospective imaging acquisitions and analyses were

performed blinded to patient study group.

CMR Protocol

Subjects underwent CMR using a clinical 1.5-T MRI scanner (Signa HD 1.5-T, GE Healthcare,

Wisconsin, USA). Sequences were acquired during breath-holds of 10 to 15 s. Initial cine CMR

sequences were performed in 3 standard long-axis (4-, 3- and 2-chamber views) and short-axis

slices (basal, mid, and apical), kept identical for each subsequent sequence throughout the CMR

examination.16 From an end-diastolic, 4-chamber, long-axis view, 5 equally spaced short-axis

slices were planned, so that the 2 outer slices lined up exactly either with the tip of the apex or

the mitral annulus. The 2 outer slices were then deleted, leaving 3 slices corresponding to typical

basal, mid, and apical short-axis views. To calculate LV volume and function, a contiguous

short-axis steady state free precession stack was acquired (8 mm slice thickness, no gap),

extending from the mitral valve annulus to the LV apex.

Delayed hyperenhancement was obtained 10 min after a bolus (0.2 mmol/kg bodyweight

to a maximum of 20 mmol) of gadolinium-diethylene triamine penta-acetic acid (Magnevist,

Schering, Germany) to identify regional fibrosis using a T1 weighted inversion-recovery gradient

echo technique (repetition time: 7.1 ms, echo time: 3.1 ms, inversion time individually

determined to null the myocardial signal; range: 180 to 250 ms, slice thickness: 8 mm, matrix:

256 × 192, number of acquisitions: 2). Delayed enhancement imaging was performed using both

standard long-axis and short axis views of the LV, including a contiguous stack of slices from

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the mitral valve annulus to the apex. For T1 mapping, all 3 standard short-axis levels were

utilized, commencing with the basal level and progressing apically.

For evaluation of diffuse interstitial fibrosis, a T1 mapping sequence described

previously17 was used to acquire images over a range of inversion times. This consisted of an

electrocardiogram-triggered, inversion-recovery prepared, 2-dimensional fast gradient echo

sequence employing variable temporal sampling of k-space (Global Applied Science Laboratory,

GE Healthcare).18 Ten images were acquired sequentially at increasing inversion times (75 to

750 ms) 15 min post-contrast over a series of 3 to 4 breath-holds using the following imaging

parameters – repetition/echo time: 3.7 ms/1.2 ms, flip angle: 20°, 256×128 acquisition matrix,

field-of-view: 36×27-cm, slice thickness: 8-mm, trigger delay: 300 ms, and views per segment:

24. Images were processed using a curve-fitting technique to generate myocardial post-contrast

T1 times as described below.

Evaluation of LV function and regional fibrosis

Volumetric analysis of the LV from which EF was derived was performed using the summation

of discs method. Left atrial volume was determined using the area-length method. Regional

fibrosis was identified by LGE within the myocardium, defined quantitatively by a myocardial

post-contrast signal intensity 5 SDs above that within a reference region of remote non-scarred

myocardium within the same slice. Myocardial delayed enhancement was considered present

only if it was identified in two orthogonal views.

Evaluation of diffuse fibrosis with T1 mapping

Following image acquisition, the 10 short-axis images of varying inversion times were analyzed

using a dedicated research software package (VizPack Version 7.2.0, Global Applied Science

Laboratory, GE Healthcare). The software enabled analysis of regions of interest (ROIs) to

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determine pixel-by-pixel and mean T1 time by fitting data acquired at various preparation times

to the exponential curve Mz(t=TI) = M0(A-Be-t/T1) relating the sample magnetization Mz observed

at time t=TI to the equilibrium magnetization M0 and sample T1, where TI denotes inversion time

for an inversion recovery experiment. For each short-axis image, an ROI was drawn around the

entire LV myocardium (excluding papillary muscles) to determine post-contrast myocardial T1

time. In addition, post-contrast T1 time was determined for the LV blood pool to serve as an

internal control using ROIs traced within the LV endocardial border. This process was repeated

to obtain myocardial and blood pool T1 times at all 3 standard short-axis levels. Post-contrast T1

time is known to be dependent on several factors including time post-gadolinium infusion and

renal function.19, 20 Because post-contrast timing was progressively greater from the basal to the

apical slices for each patient, a correction was applied to raw T1 time results individually and

according to modeling proposed by Gai and co-workers, to yield corrected T1 time indexed for a

post-contrast time of 15 min and an estimated glomerular filtration rate (eGFR) of 90 ml/min.20

For each subject, a single global corrected T1 time was calculated by averaging the corrected T1

times at each of the 3 short-axis slices.

Echocardiography

Two-dimensional echocardiography was performed on the same day as CMR using a clinical

system (Vivid 7, General Electric Vingmed, Milwaukee, WI). Images were acquired using a 3.5

MHz transducer in the standard parasternal and apical views with patients in the left lateral

decubitus position. Standard M-mode and 2D images including color Doppler data for 3

consecutive heartbeats were saved in cine loop format. Analyses were performed off-line using

commercially available software (Echopac 6.1, General Electric Vingmed).

Diastolic function was assessed using the mitral inflow pattern from pulsed-wave

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Doppler images and tissue Doppler imaging. Early (E) and late (A) diastolic filling velocities,

E/A ratio, E wave deceleration time, septal and lateral early diastolic mitral annular motion

velocity (e’), and the E/e’ ratio were assessed. The anteroposterior diameter of the left atrium

(LA) was measured at end-systole on the M-mode image obtained from the parasternal long-axis

view.

Strain Analysis

LV deformation was assessed using 2D speckle tracking strain imaging. Deformation of the LV

was determined in 3 directions: (i) radial strain, reflecting myocardial thickening/thinning in the

short-axis plane; (ii) circumferential strain, reflecting myocardial shortening/lengthening in the

short-axis plane; and (iii) longitudinal strain, reflecting myocardial shortening/lengthening in the

long-axis plane. Peak systolic radial and circumferential strain and strain rate were calculated by

averaging the peak systolic values of 18 segments, derived from the 6 segments of the 3 short-

axis views (basal, mid, and apical LV). Peak systolic longitudinal strain and strain rate were

calculated by averaging the peak systolic values of 18 segments, derived from the 6 segments of

the 3 apical views (apical long axis and 2- and 4-chamber views). Early diastolic strain rate was

calculated by averaging the values at the time of peak E for 18 segments, derived from the 6

segments of the 3 apical views. Cardiac rotation curves as mean curves of all 6 segments were

derived from basal and apical LV short-axis views. Twist and twist rate curves were generated

based on the difference between apical and basal rotation curves. Clockwise rotation was marked

as a positive value (twist) and counter-clockwise rotation as a negative value (untwist).

Statistics

All data are expressed as mean±standard deviation (SD) unless otherwise indicated.

Comparisons between 2 groups were made using Student’s t test for continuous variables and

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plane; and (iii) longitudinal strain, reflecting myocardial shortening/lengthening

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Fishers Exact test for categorical variables. For comparisons across 3 groups, 1-way analysis of

variance (ANOVA) with Bonferroni correction was used for approximately normally distributed

variables and Kruskal-Wallis test with Bonferroni correction for non-normally distributed

variables. Simple and multiple linear regressions were used to assess predictors of post-contrast

ventricular T1 time. A p value of <0.05 was considered significant, and all reported p values are

2-tailed. Analyses were conducted using SPSS software (version 17, SPSS, Chicago, Illinois).

Results

Subject Characteristics

Thirty-three patients with a history of successful ablation for incessant atrial tachycardia were

recruited (Table 1): 18 with a history of TMC (AT-Low EF) and 15 without (AT-Normal EF).

AT-Low EF and AT-Normal EF patients were recruited 56±41 and 75±28 months following

successful ablation (p=ns). Two AT-Low EF patients each had one prior attempt at ablation that

was unsuccessful before the successful ablation procedure. There were no differences in mean

pre-ablation heart rate on 24-h holter monitoring, AT symptom duration, or AT cycle length

between the two AT patient groups (p=ns). AT-Normal EF patients had an index EF of 60±7%

and did not have routine follow-up echocardiography. AT-Low EF patients had an index EF of

36±12% which was significantly lower than AT-Normal EF patients (p<0.0001, unpaired t-test)

and recovered to 56±4% by 3 months post-ablation (p<0.0001, paired t-test). A further 20

healthy control subjects were recruited for study. Healthy controls, AT-Normal EF patients, and

AT-Low EF patients had a similar age and gender distribution. At follow-up, patients were

generally free of co-morbidities. Three AT-Low EF patients were prescribed both ACE-inhibitor

-blocker therapy: 2 had developed concomitant hypertension and coronary artery disease

after index presentation, and 1 remained on the combination from the time of diagnosis of TMC.

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Of AT-Normal EF patients, 2 were prescribed ACE-inhibitor therapy only for diabetes and/or

hypertension.

CMR Findings

Results are detailed in Table 2. Of the 18 AT-Low EF patients, 2 had received implantable

cardioverter-defibrillators (ICDs) for primary prophylaxis prior to successful ablation of atrial

tachycardia, precluding CMR. Both devices were left in situ following normalization of EF and

at follow-up had never recorded ventricular arrhythmia. Remaining AT-Low EF patients had

larger indexed LV end-diastolic volume, larger indexed end-systolic volume, and lower LV EF

compared to healthy controls and AT-Normal EF patients. No subject had delayed regional

myocardial enhancement.

The time delay from gadolinium infusion to image acquisition increased overall across

the 3 short-axis planes from 22.6±2.9 min (basal LV) to 27.0±3.7 min (mid LV) and 31.4±4.6

min (apical LV) (p<0.001). However, the time delay from gadolinium infusion to image

acquisition was not significantly different between the 3 groups at each of the 3 LV short-axis

planes (p=ns for all comparisons). Following correction of T1 time for post-contrast time delay

and eGFR, there were no significant differences in post-contrast T1 time between the 3 LV short-

axis planes within each of the 3 groups (p=ns for all comparisons). Global corrected T1 time was

shorter in AT-Low EF patients compared with controls (442±53 vs 506±61 ms, p<0.05). This

difference remained significant after exclusion of apical T1 time measurements, a potential

source of error due to their smaller size and the influence of noise and patient specific delays

(440±54 vs 492±70, p<0.05).

Predictors of Ventricular T1 Time in AT-Low EF Patients

Simple and multiple linear regressions were performed to assess predictors of fibrosis as

olume, and lowerr LLLLVV

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e timmmem delay frromm gaggadolililinninn umm infuusioonnn to immagegege aaaacqccqc uiisiiitionn iincccreeasedd dd ovovo errall l aacr

-axisi ppplalalalannnnes frfff om 222222.6±66 2.22 999 9 mmmin (b(b(b(baasasa alallal LLLV)V)V)V tttto 27272727 0.000±3±3±3±3.7777 mimimimin (((midddd LLLLV)V)VV anddd 33331.111 4±4±4±4±4

l LVVVV))) (p(p(p<000 0.000101011).).). HHHowever, the iitime dddellayyy fffrom gagg ddod lililil ninininium iiinfnfnfnfusiiion to iiimamamamagegegege

tt isi ififiic tltl didiffff tt bb t tthhe 33 tat hh fof tthhe 33 LLVV hsh tt


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measured by ventricular T1 time, using the following known and putative predictors of diffuse

fibrosis: age, mean heart rate on 24-h holter monitoring, AT symptom duration, index EF, and

post-ablation follow-up duration (Table 3). Simple linear regression revealed a potential

relationship between AT symptom duration and ventricular T1 time (F=3.19, R2=0.24, p=0.1). A

significant inverse relationship between AT symptom duration and ventricular T1 time was

confirmed in the multivariate model ( =-0.79, p<0.05; adjusted R2=0.28).

Echocardiographic Findings

There were no significant differences in diastolic parameters across the 3 groups (Table 4).

Speckle tracking analysis revealed subtle differences in LV systolic and diastolic function (Table

5). Despite having recovered EF within the normal range, AT-Low EF patients showed

attenuated global circumferential strain, global longitudinal strain, and twist rate compared with

healthy controls and AT-Normal EF patients. Global early diastolic strain rate was also reduced

compared to controls. Speckle tracking analysis showed no differences between AT-Normal EF

and control subjects.

Discussion

In this study, we characterized LV structure and function in patients with a past history of TMC

induced by incessant focal atrial tachycardia, late after successful ablation of the culprit

arrhythmia. This is a unique patient cohort as long-term arrhythmia cure is feasible. Our major

findings, 5 years following successful ablation, are as follows: (i) LV indices of TMC patients

were within normal ranges on CMR, echocardiography, and strain analysis; (ii) TMC patients

showed subtle differences in LV structure and function compared with controls, with larger LV

dimensions, lower EF, and attenuated myocardial strain and twist rate; and (iii) compared to

ee 33 ggroupps (T(( abablele 4)4)4)4).

nd diaiaststololiciic fffununctctioioioionnn (

e

n d

t a

l bj

haaaviviviinngnn rrrrececee ovvverererered EF within the normal lll rarar nnge, AT-Low www EFEFFF patients showed

ggggloooobal circummfeerentnntiial stststrrrain, globoobal looongiituudiiinanaanalll stssts raiinin, andd twwwissst ratetetet comompaaareeed

ntrolsss a ddnd ATTT-NNNorm lal EFFF patients. GlGlGlobobbalal earlyll diaii stolliici str iiain ratett was allso redd

to controls. SpSpSpeckle trackinggg analyyysis showed no differreeene cesss bbbeb tween ATTTT-NoNoNoNorma

l bj


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12

controls, TMC patients had reduced global corrected T1 time consistent with diffuse myocardial

fibrosis.

Clinical studies of TMC consistently document good outcomes in the early recovery

phase with EF recovering to the normal range within 1 to 6 months of treatment.6, 8, 9, 21, 22

However, late adverse outcomes have been reported.8, 9 Among a cohort of 24 TMC patients (EF

26±9%) followed for a mean of 26 months after treatment, Nerheim and co-workers reported 5

cases of recurrent heart failure in which EF declined precipitously with recurrent tachycardia.9 In

addition, 3 relatively young males suffered unexpected sudden cardiac death at 6 months, 9

months, and years following recovery of normal EF. However, all 3 had recurrent and persistent

AF before death and one had undergone AV node ablation and pacing. Thus none of the 3 had

been cured of the index arrhythmia and the cause of death was uncertain. Nevertheless, these 3

patients had significantly depressed index EF compared to the rest of the cohort (16±5%).

Watanabe and co-workers reported similar findings among 12 TMC patients (EF 32±10%,

NYHA functional class 2.3±0.5): 2 patients experienced rapid return of systolic dysfunction with

tachycardia recurrence, and 1 patient died suddenly 40 months after EF recovery in the absence

of documented recurrent tachycardia and heart failure.8 These observations suggest that

persistent ultrastructural changes of the myocardium may provide an arrhythmogenic substrate

and predispose to LV deterioration in the face of repeated stress. Indeed, Dandamudi and co-

workers demonstrated persistent LV dilatation in 24 TMC patients up to 14 months after

appropriate treatment and normalization of EF.6

Our study revealed differences in LV structure and function in TMC patients compared

with controls years after definitive treatment of the culprit tachycardia. Our cohort is unique in

being composed of patients with TMC who were largely free of important confounding

c death at 6 monthhhhs,s,s,s, 99

ad rececururrerenntttt anandddd pepepeperrrsrsii

death and one had undergone AV node ablation and pacing. Thus none of the 3 h

of the index arrhythmia and the cause of death was uncertain. Nevertheless, the

d

a

nctional class 2 3±0 5): 2 patients e perienced rapid ret rn of s stolic d sf nction

deatataa h h hh ananand dd d onoo e ee hhhah d undergone AV node abababablalll tion and pacaa ing.g.g.g. Thus none of the 3 h

oooof fff the index ararrrhyyythhhmiaaa andddd tttthehehe ccausesee of f ddeatttthh h wwwaw ss uununccertaiain. NNNeverrrrthhhelleess, thhhe

d signgngngnifiifificiccicantlllly ddded prpressed ddd ininininddddex EFEFEFEF comoo papared dd totototo tthehehehe ressstttt ffof ttthhheh cohohohohorororo t (11116±6±6±±5%5%5%5%))).

andddd co-workekekersrrr reppportedd d siiiimilall r fififi ddnddiini gsgg amonggg 1111222 TMTMTMTMCC CC papapatitititients ((((EFEFEFE 33332±2±2±2±1010100%,

tctiio ll lcl 22 3±3±00 5)5) 22 titi tts iie ded idid tet fof ttolili dd fsf tctiio


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influences. All patients presented with incessant focal atrial tachycardia with minimal

comorbidities, underwent curative ablation, and had no recurrence at follow up. In contrast, the

majority of patients in prior TMC series have had cardiomyopathy secondary to atrial

fibrillation/flutter.7-9, 21 In these series, outcomes may have been negatively biased by the

presence of conditions associated with these arrhythmias such as pre-existing hypertension and

heart failure. Cases of atrial fibrillation were generally treated with pharmacological rate-control

or cardioversion, allowing the confounding influence of arrhythmia recurrence and unrecognized

periods of poor rate-control to bias results. Evidence of a negative impact of irregular ventricular

rhythm per se on ventricular function despite “controlled” ventricular rate also exists.21, 23 In

contrast, focal atrial tachycardia is considered a sporadic arrhythmia not known to be influenced

by pre-existing ventricular cardiomyopathy. Our patients did not experience the adverse

outcomes of recurrent heart failure and sudden death described in prior series.8, 9 In 2 patients

with severely depressed index EF who received ICD implantation for primary prophylaxis, no

ventricular arrhythmias were recorded. However, our TMC cohort had less severe systolic

impairment at presentation in comparison to these previous series and this may account for

differences in observed outcomes (index EF of 36±12% vs 28±10%, p<0.05).

TMC is well studied in porcine and canine tachypacing models, and is characterized by

spherical LV dilatation, systolic dysfunction, elevated filling pressures, diminished cardiac

output, reduced systemic vascular resistance, and neurohormonal activation.24 LV dilatation is

more pronounced for end-systolic than end-diastolic indices.25, 26 Systolic dysfunction results

from loss of myocardial contractility and contractile reserve reflected by whole heart and isolated

cardiomyocyte indices.10, 25 Following resumption of normal sinus rhythm, EF typically shows

dramatic recovery in the first 24 to 48 hours, subsequently normalizing in the following weeks.1,

ppact of irreggular vvenenenentrt

rate alalllsoso ee ixixiisttsts.s 2121211, , ,, 23232323 II

o e

s

o n

ely depressed index EF who received ICD implantation for primary prophylaxis,

arrh thmias ere recorded Ho e er o r TMC cohort had less se ere s stolic

ocaaaalll atatatatriririr alalalal tttaachyhyhyccac rdia is considered a sporororada ic arrhythmim a nonononot known to be influe

sttttinnnng g ventricularr caaardddiomymymyyopatttathyyy. Ouur pattieentsss dddidididd nnottt eeexpeeriiencnnce thee ee aada veverseee

of recucuccurrrrreeeent hehhh artttt fafff illililure anananndddd sudddddenenene ddddeaththth ddded scsccriririribebebeb ddd d innn ppppriiior serieieieesss.8888, 99 IIIIn 222 patiititien

ely yy deddd prpp essed dd inininindeddd x EFEFEF whohhh rec iieiveddd d ICCCCDDD iimi plplplantatiiionn fffor ppprirrr maryyy ppprophphphphylylyly axaaa is,

hrh tthhmiia ddedd HHo TTMCMC hoh tt hhadd lle tst loliic


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4, 26 Nevertheless, attenuation of contractile function and relaxation remain measurable at the

cellular level 4 weeks after cessation of tachypacing, and LV volumes remain elevated.10

Development of LV hypertrophy and an increase in diffuse interstitial fibrosis are also observed,

and the resulting reduction in wall stress, rather than normalization of LV geometry or myocyte

contractility, mediates improved pump function at this stage. 10-12

With the exception of LV hypertrophy, animal model findings in the early recovery phase

bear striking resemblance to those of late follow-up in the human setting as demonstrated by our

study. We made the further observation that the degree of fibrosis correlated with arrhythmia

symptom duration but not index EF, consistent with the notion that systolic dysfunction and

fibrosis run independent courses during the induction and recovery phases of TMC as observed

in animal models.

The exact mechanism by which fibrosis is induced in this setting remains to be clearly

defined. Porcine heart failure induced by rapid atrial pacing has been associated with reduced

ventricular collagen concentration, cross-linking, and fibril diameter; while cessation of rapid

pacing resulted in recovery of systolic function accompanied by increased collagen concentration

and thickened collagen weave.11, 12 Similar findings have been replicated in dogs.27 Following

induction of heart failure by rapid pacing, LV fibroblasts isolated from failing pig hearts showed

increased formation of fibrillar collagen, increased adhesion to and migration through

extracellular matrix substrates, and differences in fibroblast associated integrins.28 In a canine

model of tachypacing-induced heart failure, isolated ventricular fibroblasts exhibited increased

proliferation rates.29 Interestingly, phenotypic changes in TMC fibroblast biology appear to

remain stable for several generations of cell culture passages.28 Collectively, these observations

point to a significant and stable transformation of fibroblast phenotype in response to

related with arrhytytytthmhmhmhm

stolicc dydydyd sfffsfununctttctioioii n nnn aaanandd

n independent courses during the induction and recovery phases of TMC as obse

m

e a

o c

collagen concentration cross linking and fibril diameter; hile cessation of rap

n indnddndepepepe enennndedededentt ccccourses during the inductioioioion and recoveryrr phahahah ses of TMC as obse

mmmom ddded ls.

e exacacacacttt mmmmechhhhaniiism bbbby whihihihichchchch fibroooosisisisis iiisi iiiinddducedededed iiinin tttthhhih s seseses ttttttt inii g remamamamainininins tottt bbbbe clllea

orcine hheh art fafafaiilili ure iini dudd ceddd d bybyby rapppidididd atriaiii lll papp cinggg hhhas bbbeeeee n asasassso icii tat dedd witittth hhh rerereeduc

llll tnt titi lili knkiin dnd ffibib irill didi tet hhilil tatiio fof


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cardiomyopathy induced by rapid ventricular rates, which may explain the presence and

persistence of LV fibrosis noted in our patients.

Our finding of diffuse LV fibrosis many years after curative ablation is highly relevant,

as this may provide a substrate for late arrhythmic events proposed to account for sudden death

observed in prior series.8, 9 Extensive evidence supports the role of fibrosis in ventricular

arrhythmogenesis.30 Among sudden death autopsy series, ventricular interstitial fibrosis in the

absence of other structural abnormalities is a consistent albeit uncommon finding, affecting an

estimated 1 to 3% of cases.31-33 Murine models show a clear relationship between inducibility of

ventricular arrhythmias and degree of interstitial fibrosis.34, 35 Increased fibrosis alters tissue

electrophysiology through partial decoupling of muscle fibres, conduction slowing, zig-zag

courses of conduction propagation, localized source-sink mismatches, and conduction blocks.36-

38 Furthermore, myofibroblast coupling to cardiomyocytes through gap junction formation

imparts enhanced automaticity to cardiomyocytes when coupled to a critical number of

myofibroblasts.39

Recent whole heart studies demonstrate the role of fibrosis in modulating formation of

early afterdepolarizations (EADs) that lead to triggered activity causing ventricular fibrillation

(VF).40, 41 It is well established that oxidative stress promotes EADs and triggered activity in

isolated cardiomyocytes.42 This same stress fails to cause EADs in well-coupled, non-fibrotic

hearts due to source-to-sink mismatches arising from cell-to-cell coupling, but readily induces

ventricular tachycardia (VT) and VF in diffusely fibrotic rat and rabbit hearts.40, 41 Optical

mapping and roving glass microelectrode single cell action potential recordings revealed

triggered activity causing focal VT that degenerates within seconds to VF after the emergence of

spatially discordant action potential duration alternans leading to wavebreak, reentry and VF.30

hipp between induccibibibibili

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lasts 39

siololologogogogyyy ththththrorrougggghhh h partial decoupling of muuuscscs le fibres, cononnduuuctctctction slowing, zig-zag

cccconnnnduction prroppagggatttationn,n localalallizedeed sououurce-sssinkkkk mmmmiiisi mamaatccches, aanddd d condddduucu tioon bbbloooc

more, myymymy fofofibroblblbllasttt coupplililiingngngng to cacaaardrdrdrdioioiomymyoc tyttteseseses tthrhrhrhrooughghghgh ggap jjjjunctctctctioioioon formatttiiiion

hanceddd autommmataaa iciii itii y yy to cardididid omyoyy cyyytes hhwhen couplplpledddd ttooo o a crrritiiti icii lall numbebebeberrr r ofofofof

ll tt 393939


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Thus, the “first-hit” of ventricular fibrosis in this paradigm does not generate ventricular

arrhythmia alone but requires a “second-hit” of oxidative stress to do so.

Diffuse ventricular fibrosis in our TMC cohort may reflect an arrhythmogenic substrate

that has remained asymptomatic due to absence of an appropriate trigger. Sudden deaths in prior

reports potentially represent lethal ventricular arrhythmias triggered by the oxidative stress

associated with tachycardia recurrence,43, 44 or some other physiologic insult. Whether patients

with TMC would benefit from a period of anti-fibrotic or anti-failure pharmacotherapy remains

to be studied.

Study Limitations

Patient numbers were limited by the scarcity of cases with atrial tachycardia-induced TMC at our

centres. However, our study is the first to report on a group of TMC patients receiving definitive

cure for their inciting arrhythmias, and has a long follow-up duration. Retrospective study design

did not allow exclusion of ventricular abnormalities prior to development of arrhythmia.

Furthermore, lack of baseline CMR and strain imaging precluded temporal comparisons at

follow-up. While an antecedent cardiomyopathy causing incessant focal AT is a theoretical

consideration, we are not aware of any prior description of such a relationship in the human

literature, and the prompt resolution of systolic dysfunction following successful arrhythmia

ablation points against this possibility. Nevertheless, we cannot exclude the possibility that the

structural and ultrastructural changes we observed following resolution of systolic dysfunction in

TMC patients were present prior to the development of TMC. However, this would challenge the

current paradigm of TMC that affected patients have normal hearts prior to the development of

incessant AT, suggesting that the development of TMC requires the presence of adverse cardiac

remodeling plus the advent of incessant AT. Several AT patients with hypertension, diabetes,

m C

owever, our study is the first to report on a group of TMC patients receiving defin

e d

o

re lack of baseline CMR and strain imaging precl ded temporal comparisons at

mbberererers ss s weweweerererer limmmitiii ed by the scarcity of caseseses with atrial tataachycycycycardia-induced TMC

owwwweeeve er, our stududy iiis the ffffiirst ttoo rrrepportt ooon aa grouooupppp ofoofo TMCMM ppaatieeeentntnts recececec ivvinng dededefin

eir incncncncitititininning arrhhh tttythmhhh iaiii s, andndndnd hhhas a aaa lolololongnn ffffollllllow-uuupup dddduuratatatioioioi n. RRReR trosososospepepep ctive studddy d

ow ex lcllusioii n ofoofo ventricii lullar abnormalililities pppriiiior tto dedd velolooopmpmpmenenenent t foff arrhyhyhyththththmimimim aaa.a

ll kk fof bb leliin CMCMRR dd tst iin ii igi lcl dd dd tte lal iri tt


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coronary disease, and/or longstanding ACE-inhibitor/ -blocker therapy were included in our

analyses. Regardless, the key finding of shorter global corrected ventricular T1 time in TMC

patients versus controls remained significant after exclusion of these 5 patients (439±55 vs

506±61 ms, p<0.05). We did not confirm the presence of interstitial fibrosis histologically, but

relied on a histologically validated contrast-enhanced T1 mapping technique to determine its

presence. Although several T1 mapping methodologies have been described, the largest body of

data in cardiomyopathy patients using human histology as a reference standard has been acquired

with the post-contrast T1 technique utilised in this study.17, 45

Conclusion

TMC patients exhibit subtle changes in LV structure and function including diffuse fibrosis long

after arrhythmia cure and return to normal EF, indicating that recovery is incomplete.

Funding Sources: Dr Ling is supported by an Australian National Heart Foundation (NHF) Postgraduate Scholarship. Dr Iles is supported by an Australian National Health and Medical Research Council (NHMRC) Postgraduate Research Scholarship. Prof Kaye is supported by an NHMRC program grant. Dr Hare is the recipient of a Research Investigatorship from the Cardiac Society of Australia and New Zealand. A/Prof Kistler is the recipient of a Research Investigatorship from the Cardiac Society of Australia and New Zealand. Dr Ellims holds a co-funded NHMRC/NHF Postgraduate Scholarship. Dr Taylor is supported by a National Health and Medical Research Council program grant, and an Australian National Heart Foundation project grant. This research is supported in part by the Victorian Government’s Operational Infrastructure Funding.

Conflict of Interest Disclosures: None.

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n

s

t

S Fate Scholarship Dr Iles is s pported b an A stralian National Health and Medic

n

nnnntssss exhibit subububu ttleee chchchchanananangegegegess s inininin LLLLVVVV sstruucttturee aand d dd fuffuf ncncncn tiiiononon iiincncnc ullul dingngngn ddddififififfufuffusesese ffffibibibibrororor sis s

thmmmmiaiaia ccccurururureeee anananndd d rerereetututuurnrnnn to nononon rmrmmmal EEEEFFF,,,, inininndidididiccac tititiingngngng ttthahahahat rererer cocococ veveveveryryry iiiissss inininincocococompmpmpm lelelel teee....

Sources: DrDrDrDr LLLLininning g g g isissis sssupupupppopopop rtrtrtedededed bbbby y y y anananan AAAAusususustrtrtrralalalaliaiii n nn NaNaNaNatitiitiononono allalal HHHHeaeaeaeartrtrtrt FFFFououououndndndndatatatatioiii n (NHFtte SS hch lol hshiip DDr IIlle iis trt ded bb AA ttr laliia NNatiti lal HH ltlthh dd MMedidi


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iograaphphphhiiicic aa ddndnd with taaaachchchchycycycycarararardidididiaaaa iiiindndndn u

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m P, BBBBiriririrgegegerrr-B-B-Bototototkikikikin nn S,S,S,S PPPPiririiracacacchahhh LLLL, ,, OlOlOlOlshshshhaanskskskkyyy B.B.B.B. HHHHeaeaartrtrtrt ffffaiaiaia lulululurerere aaandndndnd sssududududdededed n n n n dededeeatatath h h h in th tachhhycyy ardididiaaaa i-inddduc dedd carddid omyoyy papp thy yy and ddd recurrentt tataaa hchhycycyccardididid a. CiCiCircululululatatata ioioioion.

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-breathing g mr imaagigigigingng1111050505055-5-5-5-1010101060606060. .

um: Intntntntrararara iiiindndndndivivivivididididuauauau llt of the effect of field strength, cardiac cycle and variation by myocardial region.

M

Turkb EB, Nazarian S, et al. T1 m of the dolinium-enhanced ocarn 0

F, Jais P, Sanders P, et al. Catheter ablation for atrial fibrillation in congestive heE l J M d 2004;351:2373 2383

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Table 1. Subject characteristics at late-follow-up.

Healthy controls(n=20)

AT-Normal EF patients

(n=15)

AT-Low EF patients

(n=18) P value†

General characteristicsAge, years 47±17 52±14 45±19 0.7Male gender, n (%) 13 (65) 8 (53) 12 (66) 0.7Resting heart rate, beats/min 64±9 64±11 67±13 0.7Estimated GFR, ml/min 97±15 94±11 103±19 0.2Height, cm 174±11 171±8 172±9 0.8Weight, kg 73±12 75±15 75±18 0.8Body mass index, kg/m2 24±3 25±4 25±5 0.4Months post-ablation - 73±28 57±41 0.2

Co-morbidities, n (%)*Coronary artery disease 0 (0) 0 (0) 2 (11) 0.2Diabetes 0 (0) 1 (7) 0 (0) 0.3Hypertension 0 (0) 2 (13) 2 (11) 0.2

Cardiac medications, n (%)*ACE-inhibitor 0 (0) 2 (13) 3 (17) 0.1

-blocker 0 (0) 0 (0) 3 (17) 0.1AT Patient characteristics

Mean pre-abation heart rate on 24-h holter (beats/min) - 115±22 127±33 0.5

Duration of tachycardia symptoms (months) - 76±59 66±102 0.8

Tachycardia cycle length (ms) - 481±90 484±130 1.0Index EF (%) - 60±6 36±12 <0.001Early post-ablation EF (%) - - 56±6 -Late post-ablation follow-upduration (months) - 75±28 56±41 0.2

*No subjects had other cardiovascular co-morbidities or were prescribed other cardiac medications. †For comparisons across 3 groups, 1-way analysis of variance (ANOVA) with Bonferroni correction was used for continuous variables. Comparisons between 2 groups were made using Student’s t test. Fishers Exact test was used for categorical variables.

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Table 2. Systolic Function, Morphology, and Fibrosis on CMR at Late Follow-up.

Healthy controls (n=20)


(n=15)

AT-Low EFpatients (n=16)*

Pvalue†

LV ejection fraction, % 64±4 65±4 60±6‡§ <0.05LV end-diastolic volume, ml 161±38 162±37 183±43 0.2LV end-systolic volume, ml 60±19 58±18 75±22 0.06LV mass, g 105±33 100±33 102±34 1.0LA volume, ml 76±19 75±17 80±23 0.4LV end-diastolic volume index, ml/m2 84±14 85±16 102±34‡§ <0.05

LV end-systolic volume index, ml/m231±7 30±8 41±11‡§ <0.01

LV mass index, g/m2 55±15 52±16 56±17 0.9LA volume index, ml/m2 41±10 39±8 45±15 0.4Delayed enhancement, n (%) 0 (0) 0 (0) 0 (0) 1.0Global corrected T1 time (ms) 506±61 480±76 442±53‡ <0.05*Of 18 AT-Low EF patients, 2 had implantable cardioverter-defibrillators precluding CMR. †One-way analysis of variance (ANOVA) with Bonferroni correction was used for continuous variables. Fishers Exact test was used for categorical variables. ‡Significant difference compared to controls. §Significant difference compared to AT-Normal EF patients.

Table 3. Univariate and Multivariate Predictors of Ventricular T1 Time in Patients with Tachycardia-mediated Cardiomyopathy.

Univariate Model Multivariate Model*B SE B P value B SE B P value

Age (years) 0.40 40.43 0.64 0.73 0.53 0.20Mean pre-ablation heart rate on 24-h holter (beats/min)

-0.56 0.54 0.33 0.18 0.44 1.00

AT symptom duration (months) -2.97 1.66 0.10 -0.38 0.14 <0.05

Index EF (%) -1.62 1.55 0.32 -0.51 1.04 0.64Post-ablation

follow-up (months) 0.27 0.37 0.48 0.50 0.25 0.07

*Adjusted R2=0.28.

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Table 4. Diastolic Parameters on Echocardiography at Late Follow-up.

Healthy controls(n=20)


(n=15)

AT-Low EF

patients (n=18)

P value

LV ejection fraction, % 66±5 66±5 60±8*† <0.01Fractional shortening, % 36±6 41±5 32±7*† <0.01Mitral E velocity, cm/s 0.7±0.2 0.7±0.1 0.7±0.2 0.2Mitral A velocity, cm/s 0.6±0.2 0.6±0.1 0.5±0.2 0.5E/A ratio 1.4±0.5 1.5±0.6 1.5±0.6 0.9Left atrial diameter, cm 3.4±0.4 3.6±0.6 3.6±0.5 0.4Mitral E wave deceleration time, ms 193±39 199±50 206±37 0.6

Septal e’ velocity, cm/s 9.0±0.6 8.9±0.6 9.3±0.9 0.9Lateral e’ velocity, cm/s 12.0±3.9 11.4±3.6 11.5±5.0 0.9Mean e’ velocity, cm/s 10.5±3.0 10.1±2.8 10.4±4.1 1.0Septal E/e’ ratio 8.7±3.0 8.6±1.5 7.7±2.8 0.5Lateral E/e’ ratio 6.5±2.0 7.0±1.9 6.4±2.2 0.7Mean E/e’ ratio 7.4±2.3 7.6±1.6 6.8±2.1 0.6

*Significant difference compared to controls. †Significant difference compared to AT-Normal EFpatients.

Table 5. Systolic and Diastolic Indices on Speckle Tracking Analysis at Late Follow-up.

Healthy controls (n=20)


(n=15)

AT-Low EFpatients (n=18)

Pvalue

Systolic functionGRS, % 44.1±11.9 41.7±13.6 38.1±14.4 0.4GRSr, 1/s 1.9±0.4 2.0±0.4 1.8±0.4 0.2GCS, % -20.8±1.5 -22.4±2.4 -17.9±3.9* <0.01GCSr, 1/s -1.5±0.3 -1.7±0.2 -1.5±0.2 0.7GLS, % -21.1±1.4 -21.4±1.9 -19.3±2.3* <0.01GLSr, 1/s -1.2±0.2 -1.2±0.2 -1.1±0.2 0.2Twist, degrees 10.8±5.5 13.1±5.2 9.2±4.3 0.6Twist rate, degrees/s 90±32 98±25 72±29*† <0.05

Diastolic functionGEDSr, 1/s 1.8±0.2 1.7±0.3 1.5±0.3* <0.05Untwist, degrees -1.8±0.9 -1.6±0.8 -2.2±1.5 0.3Untwist rate, degrees/s -88±39 -86±58 -83±40 0.9

*Significant difference compared to controls. †Significant difference compared to AT-Normal EF patients. GRS(r) – global radial strain (rate), GCS(r) – global circumferential strain (rate), GEDSr –global early diastolic strain rate, GLS(r) – global longitudinal strain (rate).

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Kaye, James Hare, Peter Kistler and Andrew TaylorLiang-han Ling, Jonathan Kalman, Andris Ellims, Leah Iles, Caroline Medi, Craig Sherratt, David

Following Successful AblationDiffuse Ventricular Fibrosis is a Late Outcome of Tachycardia-Mediated Cardiomyopathy

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