correlation between signal-averaged electrocardiogram...

1

Correlation Between Signal-Averaged Electrocardiogram and the

Histologic Evaluation of the Myocardial Substrate in Right

Ventricular Outflow Tract Arrhythmias

Running title: Santangeli et al.; SAECG and the diagnosis of RVOT arrhythmias substrate

Pasquale Santangeli, MD1; Maurizio Pieroni, MD, PhD4,6; Antonio Dello Russo, MD, PhD5;

Michela Casella, MD, PhD5; Gemma Pelargonio, MD; PhD4;

Luigi Di Biase, MD, PhD, FHRS1,2,3; Andrea Macchione, MD1;

J. David Burkhardt, MD, FACC, FHRS1; Fulvio Bellocci, MD4;Pietro Santarelli, MD4;

Claudio Tondo, MD, PhD5; Andrea Natale, MD, FACC, FHRS, FESC1,2

1Texas Cardiac Arrhythmia Institute, St. David’s Medical Center, Austin, TX; 2Dept of Biomedical Engineering, University of Texas, Austin, TX; 3Dept of Cardiology, University of

Foggia, Foggia; 4Catholic University of the Sacred Heart, Rome; 5Cardiac Arrhythmia Research Centre, Centro Cardiologico Monzino, Milan; 6Department of Cardiovascular Diseases, San

Donato Hospital, Arezzo, Italy

Corresponding author:

Andrea Natale, MD, FACC, FHRS, FESC

Executive Med Director, TX Cardiac Arrhythmia Inst at St. David’s Medical Ctr, Austin, TX,

Consulting Prof, Division of Cardio, Stanford Univ, Palo Alto, CA, Clinical Assoc Prof of Med,

Case Western Reserve Univ, Cleveland, OH, Director, Interventional Electrophysiology, Scripps

Clinic, San Diego, Sr Clinical Director, EP Services, CA Pacific Med Ctr, San Francisco, CA

3000 N. I-35, Suite 720; Austin, TX 78705

Tel: +15215448186

Fax: +15125448184

E-mail: [email protected]

Journal Subject Codes: [5] Arrhythmias, clinical electrophysiology, drugs; [171] Electrocardiology.

MMMMMMMDDDDDDD4;P;P;P;P;P;P;Pieieieieieieetrtrtrtrtrtrtro o o o o o o SaSaSaSaSaSaSantntntntntntnt

ACC,C,,,,,, F F F F F F FHRHRHRHRHRHRHRS,S,S,S,S,S,S, F F F F F FFEEEEESEE

Arrhythmia Institute, St. David’s Medical Center, Austin, Te ya ya r

Donato Hospital Arezzo Italy

Arrhythmia Institute, St. David’s Medical Center, Austin, Teering, University of Texas, Austin, TX; 3Dept of Cardiologyatholic University of the Sacred Heart, Rome; 5Cardiac Arrhyardiologico Monzino, Milan; 6Department of Cardiovascular

Donato Hospital Arezzo Italy by guest on May 7, 2018

http://circep.ahajournals.org/D

ownloaded from

http://circep.ahajournals.org/

2

Abstract:

Background - The differential diagnosis between idiopathic and cardiomyopathy-related right

ventricular outflow tract (RVOT) ventricular arrhythmias (VAs) is crucial. Signal-averaged

electrocardiogram (SAECG) abnormalities are frequent in cardiomyopathy-related RVOT-VAs,

although their pathophysiologic basis and diagnostic value in this setting are undefined. We

tested the association between SAECG and the myocardial substrate underlying RVOT-VAs.

Methods and Results - 24 consecutive patients (median age 50 [42-59] years, 12 men) with

RVOT-VAs (10 with frequent [>1,000/24h] PVCs, 14 with VTs) underwent SAECG with 40 Hz

filtering and electroanatomic mapping (EAM) with EAM-guided biopsy for characterization of

the RVOT-VAs substrate. A filtered averaged QRS (fQRS) was obtained and analyzed for fQRS

duration, low amplitude signal duration below 40 mV (LAS40) and root mean square voltage in

last 40 ms of the QRS (RMS40). Standard definition of EAM scar was used. EAM-guided

biopsy diagnosed ARVC in 11 (46%), myocarditis in 8 (33%), and idiopathic RVOT-VAs in 5

(21%) patients. Patients with cardiomyopathy-related RVOT-VAs had 1 EAM scar (median 2

[1-2], all with RVOT scar). EAM of patients with idiopathic RVOT-VAs was normal. Patients

with cardiomyopathy-related RVOT-VAs had significantly longer fQRS (106 [92-132] ms vs. 83

[82-84] ms, P = 0.01) and LAS40 (39 [36-51] ms vs. 19 [18-21] ms, P = 0.02), and lower

RMS40 (18 [9-26] V vs. 33 [32-33] V, P = 0.04). A significant linear correlation was found

between the extension (cm2) of the RVOT scar and all three SAECG parameters (rs = 0.76, P <

0.001 for the fQRSd; rs = 0.73, P < 0.001 for the LAS40; and rs = -0.72, P < 0.001 for the

RMS40). Using the established 2 of 3 criteria (i.e., late potentials) SAECG diagnosed

cardiomyopathy-related RVOT-VAs with high positive (100%) but low negative (38%)

predictive values, and missed 7/9 (78%) patients with RVOT scar <8 cm2.

Conclusions - In patients with RVOT-VAs, abnormal SAECG parameters reflect the presence of

extensive cardiomyopathic involvement of the RVOT. However, a negative SAECG does not

reliably rule out cardiomyopathy-related RVOT-VAs in the presence of a small RVOT scar.

Key words: right ventricular outflow tract tachycardia, signal-averaged electrocardiogram, three dimensional electroanatomic mapping.

arararararrar w w w w w w wasasasasasasas u u uuuuusesesesesesesed.d.ddddd EEEEEEEAAAAAAA

nd iididididididid opopopopopopopatatatatatatathihihihihihihic c cc c cc RRRRRVRVR

e

T o

y

1 a

ents with cardiomyopathy-related RVOT-VAs had 1 EAM

T scar). EAM of patients with idiopathic RVOT-VAs was no

y-related RVOT-VAs had significantly longer fQRS (106 [9

1) and LAS40 (39 [36-51] ms vs. 19 [18-21] ms, P = 0.02), a

by guest on May 7, 2018


ownloaded from


3

Introduction

Right ventricular outflow tract ventricular arrhythmias (RVOT-VAs) are the most common

variant of nonischemic VAs.1, 2 The majority of RVOT-VAs has an idiopathic origin with a

benign clinical course;2 however, they may also represent an early manifestation of potentially

life-threatening structural heart diseases, such as myocarditis or arrhythmogenic right ventricular

cardiomyopathy (ARVC).3 Accordingly, syncope and sudden cardiac death have been reported

in patients presenting with RVOT-VAs and an apparently normal heart.4-6 An accurate

distinction between idiopathic and cardiomyopathy-related RVOT-VAs carries important clinical

and prognostic implication. Unfortunately, such distinction is often challenging especially in

early and segmental forms of ARVC, or in focal myocarditis, which may selectively affect the

RVOT without other evidence of RV involvement. The signal-averaged electrocardiogram

(SAECG) is a quick and inexpensive test to disclose areas of slow and fragmented conduction in

the RV associated with underlying cardiomyopathic substrates.7

Accordingly, SAECG abnormalities (i.e., late potentials) are frequently encountered in

patients with cardiomyopathy-related RVOT-VAs.7-9 However, the pathophysiologic

significance and diagnostic reliability of SAECG abnormalities in the setting of cardiomyopathy-

related RVOT-VAs are still undefined.

Recent studies have shown that three-dimensional electroanatomic voltage mapping

(EAM) with EAM-guided endomyocardial biopsy allow to reliably localize and quantify affected

RV segments in patients with different variants of cardiomyopathy-related VAs.10

The aim of this study was to establish the value of the SAECG in the differential

diagnosis between idiopathic and cardiomyopathy-related RVOT-VAs, by testing the association

Between SAECG abnormalities and the RVOT histologic substrate identified through EAM with

en challengingngngngngngng e

hichh mmmmmmmayayayayayayay s s s s ss selelelelelelelecececececececttitit v

r

e

w

r evidence of RV involvement. The signal-averaged electroc

and inexpensive test to disclose areas of slow and fragmente

with underlying cardiomyopathic substrates.7



ownloaded from


4

EAM-guided biopsy in a series of patients with RVOT-VAs.

Methods

We studied 24 patients (median age 50 [42-59] years, 12 males) with RVOT-VAs according to

standard 12-lead ECG criteria.11 All patients underwent a complete cardiovascular examination

including history, physical examination, 24-h Holter monitoring, SAECG, two-dimensional

echocardiography, and gadolinium contrast-enhanced cardiac magnetic resonance (CMR) (not

performed in 2 patients due to claustrophobia).

Diagnosis of ARVC was established according to current diagnostic criteria defined by

the European Society of Cardiology and International Society and Federation of Cardiology Task

Force.12 Diagnosis of myocarditis was established according to standardized histologic and

immunohistochemistry criteria (see below).

A structurally normal heart (i.e., idiopathic RVOT-VAs) was defined on the basis of

normal resting ECG, normal dimension and function (global and regional) of the left ventricular

(LV) and RV chambers as determined by echocardiography and CMR, absence of late

gadolinium enhancement on CMR, and normal EAM and EAM-guided biopsy.

Patients were excluded from this study if: they had atrial fibrillation or pacemaker rhythm

at the time of SAECG; they needed antiarrhythmic therapy at the time of SAECG and EAM; the

noise level of the SAECG was 0.5 mV.

Signal-averaged electrocardiogram

The SAECG was obtained with an Arrhythmia Research Technology-101 or 1200 System, with

bidirectional Butterworth filtering (40 to 250 Hz), as previously described.13 The following

quantitative SAECG variables of the filtered QRS were evaluated: 1) total duration (fQRSd), 2)

diagnostic crritititititititee

d FFededededededederererererereratatatatattatioioioioioioion n n n n nn ooooofofo

o t

t

y

of myocarditis was established according to standardized hist

try criteria (see below).

y normal heart (i.e., idiopathic RVOT-VAs) was defined on



ownloaded from


5

duration of the low-amplitude signals (<40 mV) in the terminal portion (LAS40), and 3) root-

mean-square voltage of the last 40 ms (RMS40). Between 300 and 500 QRS complexes were

averaged for each recording to reach a noise level <0.5 mV. Ventricular late potentials were

considered positive when 2 of the following criteria were fulfilled:7, 14, 15 1) fQRSd >114 ms, 2)

LAS40 >38 ms, and 3) RMS40 <20 V.

Cardiac magnetic resonance

Cardiac magnetic resonance was performed with a 1.5-T Signa Excite 2 scanner (General

Electric Medical Systems, Milwaukee, Wisconsin) using a cardiac 8-channel phased-array coil,

with vector ECG gating at end-expiration. Morphological evaluation of the cardiac chambers and

presence of intra-myocardial fatty infiltration were obtained by black-blood double- and triple-

inversion recovery fast spin-echo sequences (repetition time 2 RR intervals, echo time 34 ms,

slice thickness 8 mm, image matrix 256 to 256, and field of view 30 to 36 cm) along axial, short-

axis, and horizontal long-axis planes. Functional assessment was carried out using bright-blood

high-resolution steady-state free precession sequence (repetition time 3.4 ms, echo time 1.5 ms,

flip angle 50°, image matrix 224 to 288, field of view 30 to 36 cm) in axial, vertical long-axis,

horizontal long-axis, and short-axis stack. Finally, late gadolinium enhancement images were

acquired using an inversion recovery prepared breath-hold gradient-echo sequence obtained 20

min after intravenous administration of 0.2 mmol/kg gadodiamide (Omniscan, Amersham

Health, Princeton, New Jersey). Late gadolinium enhancement was reported when it was

detected in more than one imaging plane, using cross-plane localizers to confirm the position.

Post-processing was performed on an Advantage Windows Workstation using MASS

software (Medis, Leiden, the Netherlands). This software was used to view images using

standardized window width and level settings. The same software was also used for

tion of the cararrrrrrddiddddd

blackkkkkkk-b-b-b-b-b-b-blololololololoododododododod d ddddddouououououoo b

fa o

m l

long-axis planes. Functional assessment was carried out usin

fast spin-echo sequences (repetition time 2 RR intervals, echo

m, image matrix 256 to 256, and field of view 30 to 36 cm) al

long-axis planes. Functional assessment was carried out usin



ownloaded from


6

measurement of RV end-diastolic and end-systolic diameter. Cardiac magnetic resonance

analysis was performed by an expert radiologist with Society of Cardiovascular Magnetic

Resonance level-3 experience, who was blinded to the clinical, SAECG, and endomyocardial

biopsy data.

Invasive study

All patients were submitted to coronary and left and right ventricular angiography (right and left

anterior oblique views), three-dimensional EAM, and EAM-guided endomyocardial biopsy. In

particular RV angiography was performed before EAM to provide RV silhouette in two views,

thus improving the anatomical accuracy of EAM. On the basis of EAM, endomyocardial

biopsies were withdrawn from areas presenting electrical abnormalities, as previously shown.10

Three-dimensional electroanatomic mapping

All patients underwent high-density RV three-dimensional electroanatomic voltage mapping

with the CARTOTM system (Biosense-Webster, Diamond Bar, CA). Mapping points were

sampled with a 7-Fr 3.5-mm irrigated tip Navi-Star ThermocoolTM catheter (Biosense-Webster,

Diamond Bar, CA) to generate an accurate three-dimensional electroanatomic map of the RV,

reflecting the shape evidenced by angiography. High-density mapping was obtained in sinus

rhythm, and the voltage maps were edited setting the point density (fill threshold) at 15 mm and

manually eliminating intracavitary points.10 Adequate catheter contact was confirmed by

concordant catheter tip motion with the cardiac silhouettes on fluoroscopy and by adherence of

voltage map to frozen angiographic right ventricular shape. In addition, to avoid low voltage

recordings due to poor contact, the following tools were used: 1) the signal had to satisfy the

three stability criteria automatically detected by the CARTOTM system in terms of cycle length,

local activation time and beat-to-beat difference of the location of the catheter (<2%, <3 ms, and

f EAM, endomymymymmymm

malititiiiiiiesesesesesess, , , , , ,, asasasasasasas p p p p p pprererererererevvvvviviv

e

e a

system (Biosense-Webster, Diamond Bar, CA). Mapping po

electroanatomic mapping

ent high-density RV three-dimensional electroanatomic volta

system (Biosense-Webster, Diamond Bar, CA). Mapping po



ownloaded from


7

<4 mm, respectively); 2) both bipolar and unipolar signals were simultaneously acquired to

confirm true catheter contact through the analysis of local electrograms (in particular the shape

of the unipolar electrograms); 3) in the presence of a low voltage area, at least 3 additional points

were further acquired at the same site to confirm the reproducibility of the voltage measurement.

The color display to identify normal and abnormal voltage myocardium ranged from red,

indicating electroanatomic scar tissue (amplitude <0.5 mV), to purple, indicating electroanatomic

normal tissue (amplitude 1.5 mV). Intermediate colors represented the electroanatomic border

zone (signal amplitudes between 0.5 and 1.5 mV). The CARTOTM-incorporated surface area

calculation tool was used to measure the extension of RV electroanatomical scars. The

anatomical distribution of the pathological areas was evaluated dividing the RV voltage map into

five areas: 1) the outflow tract; 2) the free (anterolateral) wall; 3) the apex; 4) the

inferior/posterior wall (including the inferior and posterior basal segments); and 5) the septal

wall. According to previous studies, “electroanatomic scar” was defined as an area including at

least 3 adjacent points with bipolar signal amplitude <0.5 mV; the reference value for normal

endocardium was set at 1.5 mV as previously described for the identification of normal and

scarred areas.10

Endomyocardial biopsy, histology and immunohistochemistry

Right ventricular endomyocardial biopsies (4-5 samples from each patient) were obtained via the

femoral vein with the use of a preformed long sheath and a disposable bioptome (Cordis,

Johnson and Johnson, FL, USA). Once EAM was completed, the mapping catheter’s tip was

directed against abnormal voltage areas and the distal end of the sheath was placed close to it.

Sheath position was checked in right and left anterior oblique view and then biopsies were

withdrawn from wall segments with abnormal voltage, as previously shown.10 In case of normal

anatomical scccccararaaaaa

ivididididiididingngngngngngng t t t t tthehehehehehehe R RRRRRRV V VVVVV v

tflow tract 2) the free (anterolateral) wall 3) the a 4) the

a

p r

tflow tract; 2) the free (anterolateral) wall; 3) the apex; 4) the

all (including the inferior and posterior basal segments); and

previous studies, “electroanatomic scar” was defined as an ar



ownloaded from


8

EAM, endomyocardial biopsies were withdrawn from conventional sites including apex and

interventricular septum.

Two to three samples were processed for histology and immunohistochemistry. For

histology, multiple 5- m-thick sections were cut and stained with hematoxylin-eosin, Miller’s

elastic Van Gieson, Masson’s trichrome, and examined by light microscopy.

Immunohistochemistry for the characterization of inflammatory infiltrates was performed using

the following antibodies: CD3, CD8, CD45RO, CD68, (Dako Corporation, Glostrup, Denmark),

as previously described.10, 16-18 To quantify the inflammatory infiltrates, CD8+ and CD45RO+

positive lymphocytes were counted per high-power field (400-fold magnification) in all available

fields, and the mean number was calculated, as previously described.16-18 In patients presenting

histologic evidence of fibro-fatty replacement, a histomorphometric analysis was performed on

Masson’s trichrome-stained sections to calculate the extent of myocardial atrophy and fibro-fatty

replacement. Images obtained at 5× magnification with a digital camera (Leica DFC 420C, Leica

microsystems, Switzerland) were stored as TIFF files and analyzed with a dedicated imaging

software (Leica Application Suite v3.0, Leica microsystems, Switzerland) to calculate the

percent area occupied by adipose tissue, replacement fibrosis and residual myocardium. The

diagnosis of myocarditis was based on Dallas criteria and immunohistochemistry:19 in particular

a T-lymphocyte infiltration (>7/mm2) in the presence of cytotoxic (CD8+) and activated

(CD45RO+) lymphocytes, was considered diagnostic.20 The diagnosis of ARVC was made on

the basis of extensive fibro-fatty myocardial atrophy with a percentage of fat >3% and fibrous

tissue >40% associated with amounts of residual myocytes <45% of the specimen at

morphometric analysis.21

Statistical analysis

ld magng ificattiiiiiiiononooooo

bed.......16-16-1818 I I I I I I In n nnnnn papapapapapapattittt e

o s

- h

s D

of fibro-fatty replacement, a histomorphometric analysis was

-stained sections to calculate the extent of myocardial atrophmm

s obtained at 5× magnification with a digital camera (Leica D



ownloaded from


9

Between-group comparisons were assessed by the unpaired t-test or Mann-Whitney U test, as

appropriate, and proportions were compared by Fisher’s exact test. Bivariate linear correlations

analyses were assessed with the Spearman’s rank correlation coefficient. The diagnostic

performance of late potentials and, separately, of different SAECG parameters in diagnosing

cardiomyopathy-related RVOT-VAs was evaluated computing the sensitivity, specificity,

positive and negative predictive values with their 95% confidence interval (CI). The best cut-off

value of each SAECG parameter for the diagnosis of cardiomyopathy-related RVOT-VAs was

assessed by means of a receiver operating characteristic (ROC) analysis. Data are reported as

median (interquartile range), unless differently indicated. A level of P < 0.05 was considered for

statistical significance. Statistical analyses were done by STATA 11.2 software package (Stata

Corporation, College Station, Texas, USA).

Results

Clinical features and non-invasive findings

Clinical characteristics and noninvasive findings of the patient population are summarized in

Table 1. Spontaneous RVOT-VAs (i.e., left bundle branch block pattern and inferior axis) were

documented in all patients, and included sustained monomorphic ventricular tachycardia (VT) in

6 (25%), multiple runs of nonsustained VT in 8 (33%), and frequent (i.e., >1,000/24h) premature

ventricular contractions (PVCs) in 10 (42%) patients. Overall, 17 (71%) patients presented either

one clinical, ECG or imaging abnormality suggestive of ARVC. Among these, 10 (42%) patients

presented ECG depolarization (i.e., epsilon wave or localized prolongation of the QRS complex

in right precordial leads) or repolarization (i.e., inverted T waves beyond lead V1) abnormalities,

5 (21%) major abnormalities at non-invasive imaging evaluation (two-dimensional

l of P < 0.05 wwwwwwwaaaaa

A 111.2.2.2.2222 s s s s s ssofofofofofofoftwtwtwtwtwtwtwararararararare eeeee p

ee Station, Texas, USA).



ownloaded from


10

echocardiography or CMR), and 2 (8%) had family history of ARVC. No association between

different types of presenting RVOT arrhythmia (sustained vs. nonsustained VT vs. frequent

VPBs) and presence of baseline major abnormalities at non-invasive evaluation was found (P =

0.14 for multiple comparison). Seven patients (29%) had history of unexplained syncope and

arrhythmia-related symptoms (mainly palpitations) were present in 20 patients (83%).

Electroanatomic voltage mapping results

Table 2 reports the results of the invasive study (EAM and EAM-guided endomyocardial

biopsy). Nineteen patients (79%) had an abnormal voltage map, presenting at least one area

(median 2 [1-2]) with contiguous bipolar electrograms with voltage values < 0.5 mV (scar tissue)

surrounded by a larger zone with signal amplitudes comprised between 0.5 and 1.5 mV

indicating abnormal myocardium. The RVOT was involved in all 19 patients with abnormal

EAM, and the RV free wall represented the second most frequently affected segment (10/19

cases, 53%). Focal involvement of the RVOT was present in 5/19 (26%) patients, with a median

scar extension of 10 (9-17) cm2. The remaining 14 patients presented a more diffuse RV

involvement (2 RV segments in 11 cases, and 3 RV segments in 3 cases), corresponding to a

median scar extension of 28 (12-46) cm2.

Endomyocardial biopsy findings and final diagnosis of the RVOT-VAs substrate

In 11/19 (58%) patients with abnormal EAM, the presence of myocardial atrophy and fibro-fatty

replacement at EAM-guided endomyocardial biopsy definitely established the diagnosis of

ARVC according to current diagnostic criteria (Tables 2 to 4). In the remaining 8/19 (42%)

cases with abnormal EAM, histology showed the presence of inflammatory infiltrates associated

with necrosis of adjacent myocytes, consistent with the diagnosis of active myocarditis according

to Dallas criteria (Tables 2 and 4). In all these patients immunohistochemistry showed

age values < 00.5.5.5.5.5.5.5

etweeenenenenenenen 0 0 0 0 0 0 .5.5.5.5.5.5.5 a a a a a aandndndndndndnd 1

t

r m

n s

myocardium. The RVOT was involved in all 19 patients wit

ree wall represented the second most frequently affected segm

nvolvement of the RVOT was present in 5/19 (26%) patients



ownloaded from


11

inflammatory infiltrates to be mainly represented by activated and cytotoxic T lymphocytes. No

patient showed histological features of sarcoidosis, granulomatous and/or giant cell myocarditis.

With the exception of being slightly older, patients with ARVC did not differ from those with

myocarditis in terms of other clinical and instrumental findings.

Finally, all 5 patients with normal EAM displayed also normal histology at

endomyocardial biopsies, which were withdrawn from conventional sites including the RV apex

and the interventricular septum. In all these patients, non-invasive evaluation showed also no

abnormality, and a final diagnosis of idiopathic RVOT-VAs was definitely established. Of note,

all patients with idiopathic RVOT-VAs presented with nonsustained VAs (i.e., frequent PVCs or

nonsustained VT), whereas 6/19 (32%) patients with cardiomyopathy-related RVOT-VAs

presented with sustained VT (P = 0.28 for comparison).

Signal-averaged ECG and the histologic substrate of RVOT-VAs

Overall, ventricular late potentials at SAECG were present in 11 patients (46%), all with

cardiomyopathy-related RVOT-VAs (7 ARVC and 4 myocarditis, P = 0.041 for comparison with

idiopathic RVOT-VAs). Of note, patients with late potentials were more likely to have history of

syncope (P = 0.023), and RV morpho-functional abnormalities at CMR (Table 1).

Patients with idiopathic RVOT-VAs had significantly shorter duration of the fQRS

complex (83 [82-84] ms vs. 106 [92-132] ms, P = 0.01) and LAS40 (19 [18-21] ms vs. 39 [36-

51] ms, P = 0.02), and significantly higher values of RMS40 (33 [32-33] V vs. 18 [9-26] V, P

= 0.04) (Figure 1). No significant differences in SAECG parameters were found between

patients with ARVC-related RVOT-VAs and those with myocarditis (fQRSd 106 [91-132] ms

vs. 106 [96-127] ms, P = 0.83; LAS40 39 [36-51] ms vs. 42 [36-68] ms, P = 0.33; RMS40 18

[15-28] V vs. 18 [8-25] V, P = 0.48, respectively).

ned VAs (i.e.,.,,,,,, f f r

pathyhyyyyyy-r-rrrrrrelelelelelele atatatatatatatededededededed R R R R RRRVV

C

l

ined VT (P = 0.28 for comparison).

CG and the histologic substrate of RVOT-VAs

late potentials at SAECG were present in 11 patients (46%),



ownloaded from


12

A significant linear correlation was found between all SAECG parameters and the

extension of RVOT cardiomyopathic involvement (i.e., cm2 of RVOT scar), with the most

significant association being observed for the fQRSd (rs = 0.76, P < 0.001) and for the LAS40 (rs

= 0.73, P < 0.001) (Figure 2). Of note, SAECG parameters were not associated with presence of

scar in other RV segments (Table 2).

Overall, presence of late potentials at SAECG diagnosed cardiomyopathy-related RVOT-

VAs with a sensitivity of 58% (95% CI 38% to 78%), a specificity of 100%, a very high positive

predictive value (100%), but relatively low negative predictive value (38% [95% CI 19% to

58%]), since late potentials were absent in 8/19 (42%) patients with cardiomyopathy-related

RVOT-VAs (4 ARVC and 4 myocarditis). The presence of late potentials was associated with

higher extension of electroanatomic scar in the RVOT (13 [9-17] cm2 vs. 5 [4-6] cm2, P = 0.01),

and late potentials were absent in 7/9 (78%) patients with RVOT scar <8 cm2. Accordingly, at

ROC analysis, an extension of electroanatomic scar 8 cm2 was found the best predictor of

positive late potentials (sensitivity 91%, specificity 92%).

When analyzed according to established cut-off values (i.e., fQRSd >114 ms; LAS40 >38

ms, and RMS40 <20 V), all three individual SAECG parameters showed high specificity

(100%) for the diagnosis of cardiomyopathy-related RVOT-VAs. However, the sensitivity

ranged from 37% (95% CI 18% to 56%) for the fQRSd, to 58% (95% CI 38% to 78%) for the

LAS40 and RMS40. The sensitivity of the fQRSd reached 74% (95% CI 56% to 91%) without

affecting the 100% specificity adopting a cut-of value of 100 ms, while the established cut-off

values for LAS40 and RMS40 were confirmed the best cut-off values also at ROC analysis.

Adopting a cut-off value to define abnormal fQRSd of 100 ms, the recalculated

sensitivity and negative predictive value of late potentials (i.e., at least 2 abnormal SAECG

with cardiomyyopopopopopopopa

potennnnnnntitititititiialalalalalala s s sssss wawawawawawawas s s s s s s asa

e

w

x p

electroanatomic scar in the RVOT (13 [9-17] cm2 vs. 5 [4-6]

were absent in 7/9 (78%) patients with RVOT scar <8 cm2. A

xtension of electroanatomic scar 8 cm2 was found the best p



ownloaded from


13

parameters) to diagnose cardiomyopathy-related RVOT-VAs reached 84% (95% CI 70% to

99%) and 63% (95% CI 43% to 82%), respectively, while the specificity and positive predictive

value remained high (100%) (Figure 3).

Discussion

The differential diagnosis between idiopathic and cardiomyopathy-related RVOT-VAs is a major

clinical challenge for cardiologists; RVOT-VAs may represent the early manifestation of

concealed cardiomyopathies that can unpredictably lead to sudden cardiac death in the absence

of overt structural RV abnormalities.4-6 The SAECG is a quick and inexpensive diagnostic tool to

disclose the presence of pathologically slow conduction areas in the RV (i.e., late potentials) due

to underlying cardiomyopathic substrates.7, 12, 15 Although SAECG abnormalities have been

described in patients with cardiomyopathy-related RVOT-VAs,7, 10, 15 their pathophysiologic

basis and diagnostic relevance are still undefined.

The present study elucidates the pathophysiologic basis of SAECG abnormalities in

patients with RVOT-VAs, showing that they correlate with the extent of the pathologic

involvement of the RVOT by cardiomyopathic substrates. Of note, epsilon waves at surface

ECG, which represent the macroscopic manifestation of late potentials at SAECG, were found in

3 patients in the ARVC group who had significantly larger RVOT scars compared to those

without epsilon waves. This finding is in line with seminal experiences on endocardial mapping

of epsilon waves in ARVC.22

Presence of late potentials was strikingly associated with cardiomyopathy-related RVOT-

VAs, and such association was observed independently from the underlying histologic substrate

identified through EAM-guided endomyocardial biopsy (i.e., ARVC or myocarditis). The

nd inexpensiveveeeeee d

the RRRRRRRV V V V V VV (i(i(i(i(i(i(i.e.e.e.e.e.e.e.,.,.,.,.,.,., l l l l l l laaaatataa e

m s

s o

myopathic substrates.7, 12, 15 Although SAECG abnormalities

s with cardiomyopathy-related RVOT-VAs,7, 10, 15 their patho

relevance are still undefined.



ownloaded from


14

clinical overlap between these two clinical entities has been well-reported in recent years;10, 23, 24

the present study shows that such overlap may extend also to SAECG abnormalities, which

could be caused by either slow conduction due to fibro-fatty tissue, as it is the case for ARVC, or

to underlying myocardial inflammation, as it is the case for myocarditis. Importantly, a

significantly higher prevalence of late potentials was found among patients with history of

previous syncope, further supporting the concept that SAECG abnormalities in these patients

underlie potentially life-threatening cardiomyopathic substrates. Indeed, syncope has been

consistently demonstrated an ominous predictor of sudden cardiac death in patients with RV

cardiomyopathy.25 Moreover, late potentials were associated with a higher prevalence of RV

dilatation and dysfunction, which is consistent with previous studies.9 While the presence of late

potentials was strikingly associated with underlying RVOT cardiomyopathic substrates, absence

of SAECG abnormalities did not reliably rule out RVOT pathologic involvement, since 7/9

patients with a small RVOT scar (i.e., <8 cm2) actually displayed normal SAECG. These

findings account for a high specificity and positive predictive value, but relatively low sensitivity

and negative predictive value of SAECG in diagnosing cardiomyopathy-related RVOT-VAs,

which is in line with recent data on SAECG in ARVC.15

At ROC analysis, the diagnostic performance of individual SAECG parameters adopting

established cut-off values appeared optimal for the LAS40 and RMS40, but suboptimal for the

fQRSd. However, the diagnostic sensitivity of the fQRSd increased from 37% (95% CI 18% to

56%) to 74% (95% CI 56% to 91%) after decreasing the cut-off value to define abnormal fQRSd

from 114 ms to 100 ms. Although the results of our ROC analysis should be interpreted with

caution due to the small sample size of our patient population, they may also suggest that

different cut-off values for the fQRSd may be necessary to improve the diagnostic performance

h a higher preevavavvvvv

dies..9999999 W W W W W WWhihihihihihihilelelelelelele t t t t t tthehehhhhh

n b

l n

l G

ngly associated with underlying RVOT cardiomyopathic sub

lities did not reliably rule out RVOT pathologic involvemen

l RVOT scar (i.e., <8 cm2) actually displayed normal SAECG



ownloaded from


15

of SAECG in the setting of RVOT-VAs. To this regard, it is important to emphasize that the

current cut-off values for late potentials have been derived from studies in patients with ischemic

cardiomyopathy after acute myocardial infarction.14

Clinical implications

The significant correlation between SAECG abnormalities and cardiomyopathic involvement of

the RVOT, whatever the underlying pathological substrate, may have important clinical

implication, particularly in segmental and early forms of ARVC and in younger patients with

ventricular arrhythmias due to focal myocarditis and mild or absent RV abnormalities. On the

basis of the observed high positive predictive value, the detection of abnormal SAECG

parameters during the noninvasive workup of patients with RVOT-VAs should raise the

suspicion of underlying cardiomyopathic substrates and point to further investigation. On the

other hand, absence of late potentials does not reliably rule out the presence of small RVOT

scars reflecting underlying pathologic substrates, at least when adopting current cut-off values

for defining abnormal SAECG parameters.

In these cases, EAM with EAM-guided endomyocardial biopsy appears important to

reach a definite diagnosis of substrate, especially in the presence of peculiar clinical features

such as family history of ARVC, sustained VAs, or typical ECG depolarization/repolarization

abnormalities. Indeed, in our study no other non-invasive diagnostic tool, including contrast-

enhanced cardiac magnetic resonance, was able to distinguish between patients with ARVC-

related VAs and those with myocarditis. The definite diagnosis of the substrate underlying

RVOT-VAs might have important clinical consequences on the therapeutic approach (e.g.,

ablation, ICD, drugs), prognosis, and familial screening (indicated in the presence of a diagnosis

of ARVC).

n of abnormall S SS S SSSA

T-VAVAVAVAVAVAVAs s sss s shshshshshhshouououououououldldldldldldld r

y a

m

e

ying cardiomyopathic substrates and point to further investiga

of late potentials does not reliably rule out the presence of sm

erlying pathologic substrates, at least when adopting current



ownloaded from


16

On the other hand, our study suggests also that the sensitivity and negative predictive

value of the SAECG may significantly increase when adopting a cut-off value for defining

abnormal fQRSd of 100 ms, and this finding warrants a prospective validation in properly

designed studies.

Study limitations

This study included a relatively small sample of patients who underwent an extensive diagnostic

study protocol, including EAM and EAM-guided endomyocardial biopsy. As such, caution

should be exercised in generalizing our findings to a larger and unselected cohort of patients with

RVOT-VAs, especially the computations on the diagnostic performance of the SAECG in

diagnosing cardiomyopathy-related RVOT-VAs.

It is also important to emphasize that our Institution is a tertiary center for the study of

arrhythmic manifestations of cardiomyopathies, and many patients with clinical suspicion of

underlying cardiomyopathic substrates (e.g., family history of sudden death,

depolarization/repolarization abnormalities at the 12-lead ECG) are usually sent from other other

Institutions or referring physicians. Therefore, a possible referral bias may also have influenced

the features of study population.

Finally, our cohort of patients with cardiomyopathy-related RVOT-VAs consisted only of

patients with ARVC and myocarditis. Whether our results may be generalized also to patients

with RVOT-VAs and underlying myocardial substrates other than that reported in our series

(e.g., sarcoidosis, Chagas cardiomyopathy, or myocardial infarction) warrants further

investigation.

Conclusions

In patients with RVOT-Vas, abnormal SAECG parameters reflect the presence of

rmance of the e e e ee SSSSS

o

a

y

ortant to emphasize that our Institution is a tertiary center fo

ations of cardiomyopathies, and many patients with clinical

yopathic substrates (e.g., family history of sudden death,



ownloaded from


17

cardiomyopathic involvement of the RVOT, and should prompt to perform further diagnostic

investigations, including EAM with EAM-guided biopsy, to identify the underlying myocardial

substrate. Our findings clarify the pathophysiologic basis of SAECG abnormalities in such

patients, and provide an explanation to the observed high specificity but low sensitivity of late

potentials in diagnosing cardiomyopathy-related RVOT-VAs. With the current cut-off values to

define abnormal SAECG parameters, most patients with small RVOT areas of cardiomyopathic

involvement (i.e., <8 cm2) are missed. The diagnostic sensitivity of SAECG in detecting

cardiomyopathy-related RVOT-VAs may significantly increase (16/19 [84%] patients correctly

diagnosed) considering a value of the fQRSd 100 ms as abnormal. Such findings, if confirmed

in larger series, could lead to redefine the relevance of SAECG in the differential diagnosis

between idiopathic and cardiomyopathy-related RVOT-VAs.

Funding Sources: This study was partially supported by a Telethon Foundation Grant (GGP10186 to M.P.).

Conflict of Interest Disclosures: Dr. Andrea Natale has received consultant fees or honoraria from Biosense Webster, Boston Scientific, Medtronic, Biotronic, and LifeWatch. Dr. Claudio Tondo has served as a member of the advisory board of Biosense Webster and has been a consultant for and received lecture fees from St. Jude Medical. Dr. Luigi Di Biase has received consultant fees from Biosense Webster and Hansen Medical.

References:

1. Buxton AE, Waxman HL, Marchlinski FE, Simson MB, Cassidy D, Josephson ME. Right ventricular tachycardia: clinical and electrophysiologic characteristics. Circulation. 1983;68:917-927. 2. Lerman BB, Stein K, Engelstein ED, Battleman DS, Lippman N, Bei D, Catanzaro D. Mechanism of repetitive monomorphic ventricular tachycardia. Circulation. 1995;92:421-429. 3. Marcus FI, Fontaine GH, Guiraudon G, Frank R, Laurenceau JL, Malergue C, Grosgogeat Y. Right ventricular dysplasia: a report of 24 adult cases. Circulation. 1982;65:384-398.

mal. Such findiiiiiingnnnnnn

n thhe e e e ee e dididididididiffffffffffffferererererererenenenenenenentititititititia

a

T)

and cardiomyopathy-related RVOT-VAs.

This study was partially supported by a Telethon Foundation ).



ownloaded from


18

4. Pedersen DH, Zipes DP, Foster PR, Troup PJ. Ventricular tachycardia and ventricular fibrillation in a young population. Circulation. 1979;60:988-997. 5. Lesch M, Lewis E, Humphries JO, Ross RS. Paroxysmal ventricular tachycardia in the absence of organic heart disease. Report of a case and review of the literature. Ann Intern Med. 1967;66:950-960.

6. Maddox K. Intermittent ventricular tachycardia in youth: report of case with fatal termination. Am Heart J. 1947;33:739-740. 7. Santangeli P, Infusino F, Sgueglia GA, Sestito A, Lanza GA. Ventricular late potentials: a critical overview and current applications. J Electrocardiol. 2008;41:318-324. 8. Nasir K, Rutberg J, Tandri H, Berger R, Tomaselli G, Calkins H. Utility of SAECG in arrhythmogenic right ventricle dysplasia. Ann Noninvasive Electrocardiol. 2003;8:112-120. 9. Nava A, Folino AF, Bauce B, Turrini P, Buja GF, Daliento L, Thiene G. Signal-averaged electrocardiogram in patients with arrhythmogenic right ventricular cardiomyopathy and ventricular arrhythmias. Eur Heart J. 2000;21:58-65. 10. Pieroni M, Dello Russo A, Marzo F, Pelargonio G, Casella M, Bellocci F, Crea F. High prevalence of myocarditis mimicking arrhythmogenic right ventricular cardiomyopathy differential diagnosis by electroanatomic mapping-guided endomyocardial biopsy. J Am Coll Cardiol. 2009;53:681-689. 11. Jadonath RL, Schwartzman DS, Preminger MW, Gottlieb CD, Marchlinski FE. Utility of the 12-lead electrocardiogram in localizing the origin of right ventricular outflow tract tachycardia. Am Heart J. 1995;130:1107-1113. 12. Marcus FI, McKenna WJ, Sherrill D, Basso C, Bauce B, Bluemke DA, Calkins H, Corrado D, Cox MG, Daubert JP, Fontaine G, Gear K, Hauer R, Nava A, Picard MH, Protonotarios N, Saffitz JE, Sanborn DM, Steinberg JS, Tandri H, Thiene G, Towbin JA, Tsatsopoulou A, Wichter T, Zareba W. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the task force criteria. Circulation. 2010;121:1533-1541. 13. Santarelli P, Lanza GA, Biscione F, Natale A, Corsini G, Riccio C, Occhetta E, Rossi P, Gronda M, Makmur J. Effects of thrombolysis and atenolol or metoprolol on the signal-averaged electrocardiogram after acute myocardial infarction. Late Potentials Italian Study (LAPIS). Am J Cardiol. 1993;72:525-531.

14. Breithardt G, Cain ME, el-Sherif N, Flowers NC, Hombach V, Janse M, Simson MB, Steinbeck G. Standards for analysis of ventricular late potentials using high-resolution or signal-averaged electrocardiography. A statement by a Task Force Committee of the European Society of Cardiology, the American Heart Association, and the American College of Cardiology. Circulation. 1991;83:1481-1488.

Thiene G. Sigiggggggnnannnnnulululllullaaaaaaarrr rrrr cacacacacacacardrdrdrdrdrdrdioioioioioioiomymymymymymymyopopopopopopopaaaaaaa

o ra ys s

hwartzman DS Preminger MW Gottlieb CD Marchlinski F

o Russo A, Marzo F, Pelargonio G, Casella M, Bellocci F, Crarditis mimicking arrhythmogenic right ventricular cardiomyrrs by electroanatomic mapping-guided endomyocardial biops1-689.

hwartzman DS Preminger MW Gottlieb CD Marchlinski F by guest on May 7, 2018


ownloaded from


19

15. Kamath GS, Zareba W, Delaney J, Koneru JN, McKenna W, Gear K, Polonsky S, Sherrill D, Bluemke D, Marcus F, Steinberg JS. Value of the signal-averaged electrocardiogram in arrhythmogenic right ventricular cardiomyopathy/dysplasia. Heart Rhythm. 2011;8:256-262. 16. Chimenti C, Calabrese F, Thiene G, Pieroni M, Maseri A, Frustaci A. Inflammatory left ventricular microaneurysms as a cause of apparently idiopathic ventricular tachyarrhythmias. Circulation. 2001;104:168-173. 17. Chimenti C, Pieroni M, Maseri A, Frustaci A. Histologic findings in patients with clinical and instrumental diagnosis of sporadic arrhythmogenic right ventricular dysplasia. J Am Coll Cardiol. 2004;43:2305-2313. 18. Frustaci A, Priori SG, Pieroni M, Chimenti C, Napolitano C, Rivolta I, Sanna T, Bellocci F, Russo MA. Cardiac histological substrate in patients with clinical phenotype of Brugada syndrome. Circulation. 2005;112:3680-3687. 19. Baughman KL. Diagnosis of myocarditis: death of Dallas criteria. Circulation.2006;113:593-595. 20. Noutsias M, Fechner H, de Jonge H, Wang X, Dekkers D, Houtsmuller AB, Pauschinger M, Bergelson J, Warraich R, Yacoub M, Hetzer R, Lamers J, Schultheiss HP, Poller W. Human coxsackie-adenovirus receptor is colocalized with integrins alpha(v)beta(3) and alpha(v)beta(5) on the cardiomyocyte sarcolemma and upregulated in dilated cardiomyopathy: implications for cardiotropic viral infections. Circulation. 2001;104:275-280. 21. Angelini A, Basso C, Nava A, Thiene G. Endomyocardial biopsy in arrhythmogenic right ventricular cardiomyopathy. Am Heart J. 1996;132:203-206.

22. Belhassen B, Caspi A, Miller H, Shapira I, Laniado S. Extensive endocardial mapping during sinus rhythm and ventricular tachycardia in a patient with arrhythmogenic right ventricular dysplasia. J Am Coll Cardiol. 1984;4:1302-1306.

23. Corrado D, Basso C, Leoni L, Tokajuk B, Bauce B, Frigo G, Tarantini G, Napodano M, Turrini P, Ramondo A, Daliento L, Nava A, Buja G, Iliceto S, Thiene G. Three-dimensional electroanatomic voltage mapping increases accuracy of diagnosing arrhythmogenic right ventricular cardiomyopathy/dysplasia. Circulation. 2005;111:3042-3050. 24. Ladyjanskaia GA, Basso C, Hobbelink MG, Kirkels JH, Lahpor JR, Cramer MJ, Thiene G, Hauer RN, MF VO. Sarcoid myocarditis with ventricular tachycardia mimicking ARVD/C. JCardiovasc Electrophysiol. 2010;21:94-98. 25. Corrado D, Calkins H, Link MS, Leoni L, Favale S, Bevilacqua M, Basso C, Ward D, Boriani G, Ricci R, Piccini JP, Dalal D, Santini M, Buja G, Iliceto S, Estes NA, 3rd, Wichter T, McKenna WJ, Thiene G, Marcus FI. Prophylactic implantable defibrillator in patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia and no prior ventricular fibrillation or sustained ventricular tachycardia. Circulation. 2010;122:1144-1152.

teria. Circulatttttttioioioiioii

hner H de Jonge H Wang X Dekkers D, Houtsmuller AB, c ru at mf

so C Nava A Thiene G Endomyocardial biopsy in arrhythm

hner H, de Jonge H, Wang X, Dekkers D, Houtsmuller AB, ch R, Yacoub M, Hetzer R, Lamers J, Schultheiss HP, Pollerus receptor is colocalized with integrins alpha(v)beta(3) and ate sarcolemma and upregulated in dilated cardiomyopathy: imdfections. Circulation. 2001;104:275-280.

so C Nava A Thiene G Endomyocardial biopsy in arrhythm by guest on May 7, 2018


ownloaded from


20

Table 1. Clinical characteristics and noninvasive findings of the overall sample and according to

results of the SAECG. Overall Sample

(n = 24) Positive LPs

(n = 11) Negative LPs

(n = 13) P*

Age, years 50 (42-59) 51 (47-64) 45 (39-54) 0.10 Sex, male 12 (50) 5 (45) 7 (54) >0.99 Presenting RVOT-VA

Sustained VT 6 (25) 5 (45) 1 (8) 0.06 Nonsustained VT 8 (33) 3 (27) 5 (38) 0.68 Frequent PVCs (>1,000/24h) 10 (42) 3 (27) 7 (54) 0.24

Family history of ARVC 2 (8) 0 (0) 2 (15) 0.48 Clinical symptoms

Cardiac arrest 0 (0) 0 (0) 0 (0) - Syncope 7 (29) 6 (55) 1 (8) 0.023 Palpitations 17 (71) 8 (73) 9 (69) >0.99 No symptoms 4 (17) 0 (0) 4 (31) 0.09

ECG abnormalities Right precordial QRS duration 110 ms 9 (38) 7 (64) 2 (15) 0.033 Epsilon wave 3 (13) 3 (27) 0 (0) 0.08 Inverted T waves beyond lead V1 4 (17) 3 (27) 1 (8) 0.30

CMR abnormalities RV dilatation 6/22 (27) 5/9 (55) 1/13 (8) 0.023 RV global dysfunction 5/22 (23) 5/9 (56) 0/13 (0) 0.005 RV delayed enhancement, % 7/22 (32) 5/9 (56) 2/13 (15) 0.07 RV ejection fraction, % 58 (50-59) 49 (49-50) 59 (58-60) <0.001 LV ejection fraction, % 60 (56-65) 60 (55-66) 60 (59-64) 0.56

Values expressed as median (interquartile range) or n (%). LPs = ventricular late potentials; RVOT-VA = right ventricular outflow tract ventricular arrhythmia; VT = ventricular tachycardia; PVC = premature ventricular contraction; CMR = cardiac magnetic resonance; RV = right ventricular; LV = left ventricular. *Comparison between “Positive LPs” and “Negative LPs”

Table 2. Invasive findings of the overall sample and according to results of the SAECG. Overall Sample

(n = 24) Positive LPs

(n = 11) Negative LPs

(n = 13) P*

Electroanatomic scar 19 (79) 11 (100) 8 (62) 0.041 N. of EAM scars 2 (1-2) 2 (1-2) 2 (0-2) 0.69 Localization of EAM

Outflow tract 19 (79) 11 (100) 8 (62) 0.041 Free wall 10 (42) 6 (55) 4 (31) 0.41 Inferior/Posterior wall 6 (25) 1 (9) 5 (38) 0.17 Septal wall 1 (4) 0 (0) 1 (8) >0.99 Apex 0 (0) 0 (0) 0 (0) -

Endomyocardial biopsy ARVC 11 (46) 7 (64) 4 (31) 0.22 Myocarditis 8 (33) 4 (36) 4 (31) >0.99 Normal myocardium 5 (21) 0 (0) 5 (38) 0.041

Values expressed as median (interquartile range), or n (%).LPs = ventricular late potentials; N. = number; EAM = electroanatomic mapping. *Comparison between “Positive LPs” and “Negative LPs”

3 3 (2(2(( 7)7))) 3333333 ( ( ( ( (( (27272727272727) ) ) )) ) )

6/22 (27) 5/9 (55)

on 5/22 (23) 5/9 (56)ement, % 7/22 (32) 5/9 (56)n, % 58 50-5 49 9-50, % 60 (56-65) 60 (55-66) nrhythmia; VT = ventricular tachycardia; PVC = premature ventricular contract o

sitive LPs” and “Negative LPs”

6/22 (27) 5/9 (55) on 5/22 (23) 5/9 (56)

ement, % 7/22 (32) 5/9 (56) n, % 58 (50-59) 49 (49-50) , % 60 (56-65) 60 (55-66) n (interquartile range) or n (%). LPs = ventricular late potentials; RVOT-VA = rrhythmia; VT = ventricular tachycardia; PVC = premature ventricular contractioright ventricular; LV = left ventricular. sitive LPs” and “Negative LPs” by guest on M

ay 7, 2018http://circep.ahajournals.org/

Dow

nloaded from


21

Table 3. Task Force diagnostic criteria in the 11 patients with biopsy-proven ARVC. Pt. # ECG abnormalities Morpho-functional abnormalities Family

history (M) Arrhythmias+ Biopsy (M)

1 M: Inverted T waves >V1. m: None.

M: None. m: None. Other: Dyssynchronous contraction of the RVOT, LGE.

No M: None m: NSVT

Fibro-fatty tissue

2 M: Inverted T waves >V1. m: None. Other: QRS (V1-V3) 110 ms.

M: None. m: None. Other: Mild RVOT dilatation, LGE.

No M: None m: Sust. VT

Fibro-fatty tissue yyyyyy yyyyy ,

3 M: None. m: None. Other: None.

M: None. m: None. Other: None.

Yes M: None m: Freq. PVCs

Fibro-fatty tissue Q ((((( )))) ,

4* M: Inverted T waves >V1. m: None. Other: QRS (V1-V3) 110 ms.

M: None. m: None. Other: Mild RVOT dilatation at ECHO.

No M: None m: Freq. PVCs

Fibro-fatty tissue

5 M: Epsilon wave. m: None. Other: QRS (V1-V3) 110 ms.

M: None. m: None. Other: Mild global RV dilatation.


Fibro-fatty tissue Q ((((((( ))))))

6 M: None. m: None. Other: QRS (V1-V3) 110 ms.

M: Significant RV dilatation and dysfunction. m: None. Other: LGE.


Fibro-fatty tissue Q ((((( ))))

7 M: Epsilon wave. m: None. Other: QRS (V1-V3) 110 ms.

M: None. M: None. Other: Mild global RV dysfunction, LGE.


Fibro-fatty tissue Q ((((((( ))))))

8 M: Inverted T waves >V1. m: None. Other: None.

M: None. m: None. Other: RV free wall hypokinesia.


Fibro-fatty tissue Q ((((( )))) ggggg yyyyy ,

9* M: Epsilon wave. m: None. Other: QRS (V1-V3) 110 ms.

M: None. M: None. Other: Mild RVOT enlargement at ECHO.


Fibro-fatty tissue ypypypypypy

10 M: None. m: None. Other: None.

M: None. m: None. Other: None.

Yes M: None m: Sust. VT

Fibro-fatty tissue Q ((((((( )))))) ggggg

11 M: None. m: None. Other: QRS (V1-V3) 110 ms.

M: None. m: RV inferior wall akinesia and mild RV dilatation. Other: None.

No M: None m: NSVT

Fibro-fatty tissue

M = major criteria; m = minor criteria; Other = finding not included among current criteria. *Cardiac magnetic resonance not performed for claustrophobia. +Per study inclusion criteria, all ventricular arrhythmias had a left bundle-branch block morphology and inferior axis (i.e., RVOT origin, minor criteria). RVOT = right ventricular outflow tract; VT = ventricular tachycardia; Sust. = sustained; NSVT = nonsustained VT; PVCs = premature ventricular contractions; LGE = late gadolinium enhancement.

NNNNNNN

lc

E

N

N

ld global RV dilatation. cant RV dilatation and dysfunction.

E.

Nggggggg

N



ownloaded from


22

Table 4. Clinical features of the 19 patients with cardiomyopathy-related RVOT-VAs. ARVC(n = 11)

Myocarditis (n = 8)

P

Age, years 59 (48-68) 44 (38-53) 0.04 Sex, male 4 (36) 5 (63) 0.37 Presenting RVOT-VA

Sustained VT 4 (36) 2 (25) >0.99 Nonsustained VT 2 (18) 3 (38) 0.60 Frequent PVCs (>1,000/24h) 5 (45) 3 (38) >0.99

Family history of ARVC 2 (18) 0 (0) 0.49 Clinical symptoms

Cardiac arrest 0 (0) 0 (0) - Syncope 5 (45) 2 (25) 0.63 Palpitations 8 (73) 4 (50) 0.38 No symptoms 1 (9) 3 (38) 0.26

ECG abnormalities Right precordial QRS duration 110 ms 7 (64) 2 (25) 0.17 Epsilon wave 3 (27) 0 (0) 0.23 Inverted T waves beyond lead V1 4 (36) 0 (0) 0.10

CMR abnormalities RV dilatation 3/9 (33) 3/8 (38) >0.99 RV global dysfunction 3/9 (33) 2/8 (25) >0.99 RV delayed enhancement, % 4/9 (44) 3/8 (38) >0.99 RV ejection fraction, % 53 (50-58) 56 (49-58) 0.68 LV ejection fraction, % 60 (56-64) 60 (56-65) 0.91

Values expressed as median (interquartile range) or n (%). LPs = ventricular late potentials; RVOT-VA = right ventricular outflow tract ventricular arrhythmia; VT = ventricular tachycardia; PVC = premature ventricular contraction; CMR = cardiac magnetic resonance; RV = right ventricular; LV = left ventricular Figure Legends:

Figure 1. SAECG parameters in patients with cardiomyopathy-related and idiopathic RVOT-VAs.

Vertical bars represent milliseconds (ms) for the fQRSd and LAS40, and microvolts ( V) for the

RMS40.

Figure 2. Linear correlation between mean bipolar voltages in the right ventricular outflow tract and

signal averaged electrocardiogram variables (fQRSd and LAS-40). rs = Spearman’s correlation

coefficient.

Figure 3. Panel A: performance of late potentials ( 2 abnormal SAECG parameters) in diagnosing

cardiomyopathy-related RVOT-VAs according to established cut-off values of SAECG parameters

(fQRSd >114 ms; LAS40 >38 ms, and RMS40 <20 V). Panel B: performance of late potentials in

diagnosing cardiomyopathy-related RVOT-VAs according to cut-off values of SAECG parameters

derived from ROC analysis (fQRSd 100 ms; LAS40 >38 ms, and RMS40 <20 V).

3/9 (33) 22/8/8//4/4/4/4/4/4/4/9 9 9 9 9 9 9 (4(4(4(4(4(4(44)4)4)4)4)4)4) 3 3333 3 3/8/8/8/8/8/8/83 (50000000-5-5-5-5-5-5-58)8)8)8)8)8)8) 5 55 5 5 5 56 6 6 6 6 6 6 (4(4(4(4(4(4(40 (566-6-6-6-6-6-6-64)4)4)4)4)4)4) 66 6 6 6 660 0 0 0 000 (5

(interquartile range) or n (%). LPs = ventricular late potentials; RVOT-Vh n(interquartile range) or n (%). LPs = ventricular late potentials; RVOT-V

hythmia; VT = ventricular tachycardia; PVC = premature ventricular contt RV = right ventricular; LV = left ventricular



ownloaded from




ownloaded from


Tondo and Andrea NataleLuigi Di Biase, Andrea Macchione, J. David Burkhardt, Fulvio Bellocci, Pietro Santarelli, Claudio Pasquale Santangeli, Maurizio Pieroni, Antonio Dello Russo, Michela Casella, Gemma Pelargonio,

Myocardial Substrate in Right Ventricular Outflow Tract ArrhythmiasCorrelation Between Signal-Averaged Electrocardiogram and the Histologic Evaluation of the

Print ISSN: 1941-3149. Online ISSN: 1941-3084 Copyright © 2012 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 March 15, 2012;Circ Arrhythm Electrophysiol.

http://circep.ahajournals.org/content/early/2012/03/15/CIRCEP.111.967893World Wide Web at:

The online version of this article, along with updated information and services, is located on the

http://circep.ahajournals.org//subscriptions/

is online at: Circulation: Arrhythmia and Electrophysiology Information about subscribing to Subscriptions:

http://www.lww.com/reprints Information about reprints can be found online at: Reprints:

document. Permissions and Rights Question and Answerinformation about this process is available in the

requested is located, click Request Permissions in the middle column of the Web page under Services. FurtherCenter, not the Editorial Office. Once the online version of the published article for which permission is being

can be obtained via RightsLink, a service of the Copyright ClearanceCirculation: Arrhythmia and Electrophysiology Requests for permissions to reproduce figures, tables, or portions of articles originally published inPermissions:



ownloaded from

http://circep.ahajournals.org/content/early/2012/03/15/CIRCEP.111.967893

http://www.ahajournals.org/site/rights/

http://www.lww.com/reprints

http://circep.ahajournals.org//subscriptions/


correlation between signal-averaged electrocardiogram...

Documents