prediction of life-threatening ventricular arrhythmia in

J A C C : C A R D I O V A S C U L A R I M A G I N G V O L . 1 1 , N O . 1 0 , 2 0 1 8

ª 2 0 1 8 T H E A U T H O R S . P U B L I S H E D B Y E L S E V I E R O N B E H A L F O F T H E A M E R I C A N

C O L L E G E O F C A R D I O L O G Y F OU N D A T I O N . T H I S I S A N O P E N A C C E S S A R T I C L E U N D E R

T H E C C B Y - N C - N D L I C E N S E ( h t t p : / / c r e a t i v e c o mm o n s . o r g / l i c e n s e s / b y - n c - n d / 4 . 0 / ) .

ORIGINAL RESEARCH

Prediction of Life-ThreateningVentricular Arrhythmia in Patients WithArrhythmogenic Cardiomyopathy
A Primary Prevention Cohort Study
Øyvind H. Lie, MD,a,b,c Christine Rootwelt-Norberg, MD,a,b Lars A. Dejgaard, MD,a,b,c Ida Skrinde Leren, MD, PHD,a,b,c

Mathis K. Stokke, MD, PHD,a,b,c Thor Edvardsen, MD, PHD,a,b,c,d Kristina H. Haugaa, MD, PHDa,b,c,d

ABSTRACT

ISS

Fro

Os

Os

pu

su

All

Ma

OBJECTIVES This study aimed to identify clinical, electrocardiographic (ECG) and cardiac imaging predictors of first-

time life-threatening ventricular arrhythmia in patients with arrhythmogenic cardiomyopathy (AC).

BACKGROUND The role of clinical, electrocardiographic, and cardiac imaging parameters in risk stratification of pa-

tients without ventricular arrhythmia is unclear.

METHODS We followed consecutive AC probands and mutation-positive family members with no documented ven-

tricular arrhythmia from time of diagnosis to first event. We assessed clinical, electrocardiographic, and cardiac imaging

parameters according to Task Force Criteria of 2010 in addition to left ventricular (LV) and strain parameters. High-

intensity exercise was defined as >6 metabolic equivalents.

RESULTS We included 117 patients (29% probands, 50% female, age 40 � 17 years). During 4.2 (interquartile range

[IQR]: 2.4 to 7.4) years of follow-up, 18 (15%) patients experienced life-threatening ventricular arrhythmias. The 1-, 2-,

and 5-year incidence was 6%, 9%, and 22%, respectively. History of high-intensity exercise, T-wave inversions $V3, and

greater LV mechanical dispersion were the strongest risk markers (adjusted hazard ratio [HR]: 4.7 [95% confidence in-

terval (CI): 1.2 to 17.5]; p ¼ 0.02, 4.7 [95% CI: 1.6 to 13.9]; p ¼ 0.005), and 1.4 [95% CI: 1.2 to 1.6] by 10-ms increments;

p < 0.001, respectively). Median arrhythmia-free survival in patients with all risk factors was 1.2 (95% CI: 0.4 to 1.9)

years, compared with an estimated 12.0 (95% CI: 11.5 to 12.5) years in patients without any risk factors.

CONCLUSIONS History of high-intensity exercise, electrocardiographic T-wave inversions $V3, and greater LV

mechanical dispersion were strong predictors of life-threatening ventricular arrhythmia. Patients without any of these

risk factors had minimal risk, whereas $2 risk factors increased the risk dramatically. This may help to make decisions

on primary preventive implantable cardioverter defibrillator (ICD) therapy. (J Am Coll Cardiol Img 2018;11:1377–86)

© 2018 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an

open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

A rrhythmogenic cardiomyopathy (AC, other-wise known as arrhythmogenic right ventricu-lar cardiomyopathy [ARVC]) is an inheritable

heart disease caused by dysfunctional cardiac

N 1936-878X

m the aDepartment of Cardiology, Oslo University Hospital, Rikshospitalet

lo University Hospital, Rikshospitalet, Oslo, Norway; cInstitute of Clinica

lo, Norway; and the dInstitute for Surgical Research, University of Oslo

blic research grant from South-Eastern Norway Health Authority and

pported by the Norwegian Research Council. Drs. Haugaa and Edvardse

other authors have reported that they have no relationships relevant to

nuscript received December 12, 2017; revised manuscript received April 1

desmosomes, resulting in fibrofatty replacement andsubsequent structural and functional alterations ofthe right ventricle (RV) and left ventricle (LV). Thedisease is characterized by high risk of life-

https://doi.org/10.1016/j.jcmg.2018.05.017

, Oslo, Norway; bCenter for Cardiological Innovation,

l Medicine, Faculty of Medicine, University of Oslo,

, Oslo, Norway. This research was supported by a

the Center for Cardiological Innovation, which is

n have licensed a patent of mechanical dispersion.

the contents of this paper to disclose.

3, 2018, accepted May 24, 2018.

http://creativecommons.org/licenses/by-nc-nd/4.0/


http://crossmark.crossref.org/dialog/?doi=10.1016/j.jcmg.2018.05.017&domain=pdf

http://creativecommons.org/licenses/by-nc-nd/4.0/

ABBR EV I A T I ON S

AND ACRONYMS

AC = arrhythmogenic

cardiomyopathy

CMR = cardiac magnetic

resonance imaging

ECG = electrocardiogram

ICD = implantable

cardioverter-defibrillator

LV = left ventricle

RV = right ventricle

SAECG = signal-averaged

electrocardiogram

TFC = Task Force Criteria

TWI = T-wave inversion

Lie et al. J A C C : C A R D I O V A S C U L A R I M A G I N G , V O L . 1 1 , N O . 1 0 , 2 0 1 8

Prediction of Ventricular Arrhythmia in AC O C T O B E R 2 0 1 8 : 1 3 7 7 – 8 6

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threatening ventricular arrhythmia and car-diac arrest in presumed healthy youngpersons. The management of patients withAC presenting with life-threatening ventricu-lar arrhythmia is well established, withplacement of implantable cardioverter-defibrillators (ICDs) as a recommended strat-egy (1). Management of patients presentingwithout life-threatening events is less welldefined, and risk stratification and selectionof patients to receive primary preventiveICDs is challenging.

SEE PAGE 1387

The diagnosis of AC is based on a complex
set of criteria according to the revised Task ForceCriteria (TFC) of 2010 (2), in which electrocardiogram(ECG) and cardiac imaging are central elements. Ad-vances in echocardiography have provided sensitiveand accurate tools for detecting cardiac abnormalities(3,4), which have been described as markers of ven-tricular arrhythmia in patients with AC (5). Echocar-diographic strain parameters are recommended aspart of a multimodality imaging approach in AC (6),but prospective studies on prognostic value are lack-ing. Furthermore, implementation of cascade genetictesting has shifted the AC population toward moreasymptomatic mutation-positive family members.These individuals are at lower risk of arrhythmicevents than probands but should still be risk stratifiedand considered for primary preventive ICD (7). Prog-nostic markers in this population are largely unde-fined. We aimed to explore incidence and predictorsof first-time life-threatening ventricular arrhythmia ina primary prevention AC cohort.
METHODS

STUDY DESIGN AND POPULATION. Patients diag-nosed with AC at Oslo University Hospital, Rik-shospitalet, Norway, between 1997 and 2017, wereevaluated consecutively for inclusion in a primaryprevention cohort study. Probands underwent ge-netic testing as described previously (8), and cascadegenetic screening was performed in family membersof mutation positive probands. Mutation negativeprobands were only included if they fulfilled a defi-nite AC diagnosis by TFC (2) and their family mem-bers were not included.

Life-threatening ventricular arrhythmia wasdefined as sustained ventricular tachycardia—runs ofconsecutive ventricular beats >100 beats for >30 s(9)—documented on 12-lead ECG, Holter or ICD moni-toring, cardiac arrest, or appropriate shock therapy

from a primary preventive ICD. Nonsustained ven-tricular tachycardia (NSVT) was defined as consecutiveruns of $3 ventricular beats >100 beats/min for <30 s(9). Syncope at or prior to diagnosis was recorded.Exercise habits at inclusion were recorded by stan-dardized interviews. The reported exercise activitieswere assigned intensity levels on the basis of theCompendium of Physical Activity of 2011 (10). High-intensity exercise was defined as physical activity >6metabolic equivalents performed regularly during aminimum of 3 consecutive years before inclusion (11).

Patients with life-threatening event at or prior tofirst contact and patients with cardiopulmonary co-morbiditywere excluded. Time to first life-threateningventricular arrhythmia was recorded prospectivelyfrom time of diagnosis of AC or from time of firstechocardiography on a GE Vivid 7 or newer scanner.End of observation was time of event, cardiac trans-plantation, death, or last clinical follow-up by October1, 2017. Written informed consent was given by allincluded patients. The study complied with the decla-ration of Helsinki and was approved by the RegionalMedical Ethics Committee of South-Eastern Norway.

ELECTROCARDIOGRAM. Twelve-lead ECG was ob-tained at inclusion (MAC 1200 or MAC 5000, GEMedical Systems, Milwaukee, Wisconsin, or CS-200,Schiller, Baar, Switzerland). In accordance with TFC,we recorded extent of T-wave inversions (TWI),presence of epsilon waves and increased terminalactivation duration (2,12) (Figure 1, lower panel).Signal-averaged ECG (SAECG) was performed at in-clusion and evaluated according to TFC 2010 (2).

ECHOCARDIOGRAPHY. All patients were examinedwith echocardiography at inclusion (Vivid 7, E9 orE95, GE, Vingmed, Horten, Norway), and datasetswere analyzed offline (EchoPac 201, GE, Vingmed) by2 independent observers blinded to clinical and ECGdata. LV ejection fraction (LVEF) was assessed by thebiplane Simpson’s method. The LV global longitudi-nal strain (GLS) was derived from speckle trackinganalyses on 2-dimensional (2D) gray-scale imageloops with >50 frames/s from the 3 apical views andexpressed as the average peak systolic strain ina 16-segment LV model (13). LV mechanical disper-sion was defined as the standard deviation of timefrom Q/R on surface ECG to peak negative strain in 16LV segments (4) (Figure 1, upper left panels).

The RV function was assessed by the RV fractionalarea change (FAC), tricuspid annular plane systolicexcursion (TAPSE), and RV longitudinal strain(RVLS), defined as the average peak systolic strain in3 free-wall RV segments (Figure 1, upper right panel).RV mechanical dispersion (RVMD) was defined as the

FIGURE 1 Echocardiographic Strain Curves and 12-Lead ECG

LV mechanical dispersion was expressed as the SD of the time from Q/R-onset on surface ECG to peak negative strain in 16 LV segments (upper left panels).

RV longitudinal strain was expressed as the average negative strain in 3 RV free wall segments (upper right panel). ECG (lower panel) was assessed for epsilon waves

(A), terminal activation duration >55 ms (B), and T-wave inversions extending $V3 (C). 2CH ¼ apical 2-chamber view; 4CH ¼ apical 4-chamber view; APLAX ¼ apical

long axis view; AVC ¼ aortic valve closure; ECG ¼ electrocardiogram; LV ¼ left ventricle; RV ¼ right ventricle.

J A C C : C A R D I O V A S C U L A R I M A G I N G , V O L . 1 1 , N O . 1 0 , 2 0 1 8 Lie et al.O C T O B E R 2 0 1 8 : 1 3 7 7 – 8 6 Prediction of Ventricular Arrhythmia in AC

1379

standard deviation from the time of Q/R on ECG topeak negative strain in 6 RV segments, including 3septal segments (5). RV dimension measures includedproximal diameter of RV outflow tract (RVOT) fromparasternal short axis view and RV basal diameter(RVD) from RV-focused apical 4-chamber view (14).The Task Force Criteria (2) were ascertained retro-spectively in patients included before 2010.CARDIAC MAGNETIC RESONANCE. Cardiac magneticresonance imaging (CMR) was performed as previ-ously reported (15) on clinical indication in a subset ofpatients at inclusion and evaluated for the presenceof diagnostic criteria according to TFC (2). In addition,we assessed RV fat infiltration, LV volumes and EF,and late gadolinium enhancement (LGE).

STATISTICS. Values were expressed as mean � SD,frequencies (%), or median (interquartile range [IQR],and compared by unpaired Student’s t-test, chi-squaretest, Fisher’s exact test, or Mann-Whitney U test, asappropriate. Incidence of life-threatening ventriculararrhythmia was calculated by dividing number ofevents by number of eligible patients at 1, 2, and 5 yearsof follow-up. The ability of a parameter to predict life-threatening arrhythmia was expressed by Harrell’s C-statistic derived from univariable Cox regression.Multivariable Cox regression was performed withmaximum3 covariates, retaining the 3 parameterswiththe highest Harrell’s C-statistic in case of multiplepossible confounders: 1) clinical characteristics: high-intensity exercise, probands status and history of

TABLE 1 Clinical Characteristics at Inclusion of 117 Patients With AC, and Comparison of Patients Without and With

Life-Threatening Ventricular Arrhythmia During Follow-Up

All (N ¼ 117) No VA (n ¼ 99) VA (n ¼ 18) p Value Adjusted HR (95% CI) p Value

Age, yrs 40 � 17 40 � 1 8 39 � 16 0.89

BSA, m2 2.0 � 0.2 2.0 � 0.2 2.0 � 0.2 0.52

Definite AC 66 (56) 52 (53) 14 (78) 0.05 *

Female 58 (50) 53 (54) 5 (28) 0.04 *

High-intensity exercise 42 (37) 28 (29) 14 (82) <0.001 4.2 (1.1–15.6) 0.04

AA medication 7 (6) 2 (2) 5 (28) <0.001 *

Amiodarone 2 (2) 0 (0) 2 (11) 0.02

Flecainide 2 (2) 1 (1) 1 (6) 0.29

Sotalol 3 (3) 1 (1) 2 (11) 0.06

Beta-blocker 36 (31) 27 (27) 9 (50) 0.06 *

Mutation 97 (83) 86 (89) 11 (65) 0.02 *

DSC 2 (2) 2 (2) 0 (0) 1.00

DSG 5 (5) 5 (5) 0 (0) 1.00

DSP 3 (3) 3 (3) 0 (0) 1.00

PKP2 87 (90) 76 (78) 11 (65) 0.26

Probands 34 (29) 20 (20) 14 (78) <0.001 5.0 (1.4–17.5) 0.01

Syncope 37 (32) 25 (25) 12 (67) 0.001 2.0 (0.7–6.0) 0.20

Values are mean � SD or n (%), unless otherwise stated. The p values are calculated by Student’s t-test, chi-square test, or Fischer’s exact test as appropriate. Adjusted HR bymultivariable Cox regression of possible confounders (p < 0.10). *We restricted the multivariable analysis to only include the 3 parameters with the highest Harrell’s C-statisticfrom univariable Cox regression.

AA ¼ anti-arrhythmic; AC ¼ arrhythmogenic cardiomyopathy; BSA ¼ body surface area; DSC ¼ desmocollin-gene; DSG ¼ desmoglein-gene; DSP ¼ desmoplakin-gene;NSVT ¼ nonsustained ventricular tachycardia; PKP2 ¼ plakophillin 2-gene; VA ¼ life-threatening ventricular arrhythmia.



1380

syncope; 2) electrocardiography:major TWI and sex; 3)echocardiography: LV mechanical dispersion, RVLS,and sex; and 4) CMR: LVEDVi, RVEF, and sex. Theoptimal cutoff values of continuous variable weredefined as the value generating the highest Harrell’s C-statistic. The parameters from the 3 separate cate-gories’ clinical characteristics, ECG, and cardiac im-aging with the highest Harrell’s C-statistic were addedto a stepwise Cox regression model. The incrementalvalue of added parameters in the prediction modelswere assessed by reclassification analysis by inte-grated diagnostic improvement (IDI) and continuousnet reclassification improvement (NRI), and the C-statistics for prediction models were compared. TheAkaike information criterion (AIC) was estimated forthe risk models. Kaplan-Meier analyses of estimatedventricular arrhythmia-free survival for the risk fac-tors were conducted, dichotomizing continuous riskmarkers at the optimal cutoff value. Competing-riskregression was conducted to assess the impact ofcompeting endpoints. Statistical analyses were per-formed using Stata/SE 14.2 (StataCorp LLC, Texas,added packages: somersd, nri); p values were 2-sided,and values <0.05 were considered significant.

RESULTS

CLINICAL CHARACTERISTICS AND INCIDENCE OF

LIFE-THREATENING VENTRICULAR ARRHYTHMIA. Of188 patients presenting at our center with definite,

borderline, or possible AC diagnosis, 7 (4%) wereexcluded due to concomitant heart disease, 61 (34%)were excluded due to life-threatening ventriculararrhythmia at or prior to presentation, and 3 (2%)were lost to follow-up. Therefore, 117 eligible patients(34 [29%] probands, 83 [71%] mutation-positive fam-ily members) were included, of whom 27 (5) and 78(14) have been reported previously. The most com-mon presenting symptoms of probands were syncope(n ¼ 18, 53%), palpitations (n ¼ 13, 38%), and chestpain (n ¼ 12, 35%).

During 4.2 years (IQR: 2.4 to 7.4 years) of follow-up, 21 (18%) patients received primary preventiveICD. Life-threatening ventricular arrhythmiaoccurred in 18 (15%) patients (14 probands, and 4family members) after 2.0 years (IQR: 0.5 to 3.5 years)of follow-up (Table 1); as documented sustainedventricular tachycardia in 11 (6 on clinical 12-leadECG, 4 below therapy zone on ICD recordings, and 1on Holter-recording) and as shock therapy from pri-mary preventive ICD in 7. The 1-, 2-, and 5-year inci-dence was 6%, 9%, and 22%, respectively, and theincidence rate was 3.1 (95% confidence interval [CI]:1.9 to 5.0) per 100 patient years. Analyses of probandsseparately showed 1-, 2-, and 5-year incidence of 21%,25%, and 57%, respectively, and an incidence rate of10.9 (95% CI: 6.3 to 18.8) per 100 patient years. Four(5%) family members experienced life-threateningventricular arrhythmias after 3.8 years (IQR: 1.3 to

TABLE 2 ECG and Imaging Parameters at Inclusion of 117 Patients With AC and Risk Markers of Life-Threatening Ventricular Arrhythmia

During Follow-Up

All (N ¼ 117) No VA (n ¼ 99) VA (n ¼ 18) p Value Adjusted HR (95% CI) p Value

Electrocardiography

Epsilon 7 (6) 7 (7) - 0.59

NSVT 23 (20) 17 (17) 6 (33) 0.11

SAECG abnor 48 (48) 39 (45) 9 (64) 0.19

fQRS, ms 115 � 13 115 � 14 117 � 9 0.58

HFLA, ms 37 � 12 37 � 13 37 � 8 0.93

RMS, mV 32 � 17 33 � 17 27 � 17 0.19

TAD >55 ms 6 (5) 6 (6) - 0.59

TWI 33 (28) 22 (22) 11 (61) 0.001 - -

Major 23 (20) 14 (14) 9 (50) <0.001 4.7 (1.9-12.0) 0.001

Minor 10 (9) 8 (8) 2 (11) 0.65

Echocardiography

EF, % (n ¼ 115) 57 � 7 58 � 5 52 � 12 0.001 *

GLS, % (n ¼ 110) �19.3 � 3.0 �19.9 � 2.4 �16.6 � 4.1 <0.001 *

LVMD, ms† (n ¼110) 41 � 18 37 � 13 62 � 25 <0.001 1.3 (1.1-1.5) 0.005

RVD, mm 40 � 7 39 � 6 45 � 7 <0.001 *

RV FAC, % (n ¼111) 42 � 9 43 � 9 34 � 8 <0.001 *

RVLS, % (n ¼108) �24.8 � 6.4 �26.1 � 5.8 �18.6 � 5.4 <0.001 1.1 (1.0-1.2) <0.05

RVMD, ms (n ¼108) 35 � 19 33 � 17 49 � 20 <0.001 *

RVOT, mm 34 � 7 33 � 6 38 � 8 0.003 *

TAPSE, mm (n ¼ 114) 21 � 5 21 � 5 17 � 5 0.003 *

CMR N ¼ 88 n ¼ 72 n ¼ 16

LGE 11 (13) 7 (10) 4 (27) 0.08 *

LVEDVi, ml/m2 88 � 24 85 � 22 114 � 22 0.007 1.1 (1.0-1.1) <0.05

LVEF 57 � 8 58 � 8 51 � 8 0.04 *

RVEDVi, ml/m2 99 � 35 98 � 34 106 � 42 0.64

RVEF 49 � 11 50 � 11 37 � 8 0.003 0.9 (0.8-1.0) 0.07

RV aneurysm 13 (15) 6 (8) 7 (47) <0.001 *

RV fat infiltration 17 (19) 12 (17) 5 (31) 0.18

RV wall abnormal 27 (31) 16 (22) 11 (69) <0.001 *

Values are n (%) or mean � SD, unless otherwise stated. The p values are calculated by Student’s t-test, chi-square test, or Fischer’s exact test as appropriate. Separatemultivariable Cox regression per category together with patient sex as possible confounder. *From echocardiography and CMR, only the parameters with the largest Harrell’sC-statistic from LV and RV in univariable Cox regression were retained in multivariable analysis, to minimize overfitting. †Hazard ratio by 10-ms increments.

AC ¼ arrhythmogenic cardiomyopathy; CMR ¼ cardiac magnetic resonance; ECG ¼ electrocardiogram; EF ¼ ejection fraction; GLS ¼ global longitudinal strain; HFLA ¼ highfrequency low amplitude duration below 40 mV; LGE ¼ late gadolinium enhancement; LV ¼ left ventricle; LVEDVi ¼ LV end-diastolic volume indexed; LVIDd ¼ LV internaldiameter in diastole; LVMD ¼ LV mechanical dispersion; RMS ¼ root mean square voltage during final 40 ms; RV ¼ right ventricle; RVD ¼ RV basal diameter; RVEDVi ¼ RV end-diastolic volume indexed; RV FAC ¼ RV fractional area change; RVLS ¼ RV longitudinal strain; RVMD ¼ RV mechanical dispersion; RVOT ¼ RV outflow tract diameter; SAECG ¼signal-averaged electrocardiogram; TAD ¼ terminal activation duration; TAPSE ¼ tricuspid annulus plane systolic excursion; TWI ¼ T-wave inversion; VA ¼ life-threateningventricular arrhythmia.


1381

8.1 years) of follow-up. Separate analyses of familymembers showed 1-, 2-, and 5-year incidence of 0%,3%, and 4%, respectively, and an incidence rate of 0.9(95% CI: 0.3 to 2.5) per 100 patient years (p < 0.001compared with probands). Two patients werecensored by noncardiac death and 1 by cardiactransplantation.

CLINICAL PREDICTORS OF LIFE-THREATENING

VENTRICULAR ARRHYTHMIA. Male sex, history ofhigh-intensity exercise, absence of AC-related muta-tion, proband status, and previous syncope werepredictors in univariable analyses of clinical markers(Table 1). High-intensity exercise was more prevalent

among male than among female patients (53% vs.21%; p ¼ 0.001).

ECG PREDICTORS OF LIFE-THREATENING VENTRICULAR

ARRHYTHMIA. ECG and SAECG were performed at thesame day as echocardiography. Major TWI was theonly predictor on ECG (Table 2, Figure 2, mid panel).SAECG was performed in 100 (91%) patients withoutRBBB, of whom 48 (48%) had abnormal findings (47had fQRSd >114 ms, 35 (35%) had RMS <20 mV, and 35(35%) patients had HFLA >38 ms).

CARDIAC IMAGING PREDICTORS OF LIFE-THREATENING

VENTRICULAR ARRHYTHMIA. Four patients (3%) hadtheir first echocardiographies performed on older

FIGURE 2 Survival Free From Life-Threatening Ventricular Arrhythmia

100

T-Wave Inversions

80

60

40

20

0

0

Log Rank, p < 0.001

4 8Years of Follow-Up

12

100

LV Mechanical Dispersion

80

60

40

20

0

0

Log Rank, p < 0.001


12

100

High-Intensity Exercise

80

60

% V

A-Fr

ee S

urvi

val

40

20

0

0

Log Rank, p < 0.001


12

≤6 METs >6 METs TWI <V3 TWI ≥V3 MD ≤45 ms MD >45 ms

94 55 1423 9 4

1 73 41 1137 18 4

1

No. at risk

71 41 1142 21 7

1

Survival curves of 117 patients with arrhythmogenic cardiomyopathy categorized by predictors of life-threatening ventricular arrhythmia with the highest Harrell’s

C-statistic from clinical characteristics, electrocardiogram, and cardiac imaging at inclusion. Patients with history of high-intensity exercise (above 6 METs) (left panel),

with precordial TWI extending $V3 (mid-panel), and with left ventricular mechanical dispersion >45 ms (right panel) had worse arrhythmic outcome than patients not

fulfilling these criteria. MD ¼ left ventricular mechanical dispersion; METs ¼ metabolic equivalents; TWI ¼ T-wave inversion; VA ¼ life-threatening ventricular

arrhythmia.



1382

scanners, and time to event was recorded from theirfirst echocardiographies on a GE Vivid 7 or newerscanners. LV speckle tracking analyses were feasiblein 110 patients (frame rate 63 [IQR: 56 to 69] and RV in108 patients (frame rate 65 [IQR: 56 to 73]). Echocar-diographic parameters of cardiac structure and func-tion were consistently worse in patients who laterexperienced life-threatening ventricular arrhythmias(Table 2). This was evident both in probands andmutation-positive family members (Online Table 1Aand 1B, respectively). LV mechanical dispersion andRVLS had the highest Harrell’s C-statistic (0.84 and0.81, respectively) and were independent predictorsin multivariable analysis (Table 2). Adding LV me-chanical dispersion to RVLS improved risk reclassifi-cation (NRI 1.05; p < 0.001 and IDI 0.24; p < 0.001).The optimal statistical cutoff for LV mechanicaldispersion was $45 ms and for RVLS worse than–23%. Kaplan-Meier analysis demonstrated unfavor-able arrhythmic outcome in patients with LV me-chanical dispersion $45 ms at inclusion (log-rank,p < 0.001, Figure 3, right panel). In a risk predictionmodel with known GLS, LV mechanical dispersionimproved the risk reclassification (Online Table 2).

CMR was available in 88 (75%) patients (35% pro-bands, 49% female, age 38 � 16 years, 0.2 [IQR: 0.0 to

0.5] years after echocardiography) of whom 16 expe-rienced subsequent life-threatening ventricular ar-rhythmias during follow-up (Table 2).

RISK PREDICTION MODEL. The parameter with thehighest Harrell’s C-statistic from clinical characteris-tics, ECG, and cardiac imaging were added to a Coxregression model (Figure 3, left panel). Adding TWI tohigh-intensity exercise significantly increased Har-rell’s C-statistic and improved risk reclassification.Adding LV mechanical dispersion to the combinationof high-intensity exercise and TWI further improvedC-statistic significantly and improved risk reclassifi-cation (Figure 3, left panel). Estimated survival freefrom life-threatening ventricular arrhythmia in pa-tients with all 3 risk factors was only 1.2 (95% CI: 0.4to 1.9) years compared with 12.0 (95% CI: 11.5 to 12.5)years in patients without any risk factors. All patientswith 3 risk factors experienced life-threatening ven-tricular arrhythmias within 2 years, whereas only 1 of44 patients without any risk factors experienced theendpoint during 218 patient years of follow-up. Therewas no significant increase in risk from no risk factorsto 1 risk factor, but a 4-fold increase from 1 to 2 riskfactors (hazard ratio [HR]: 4.1, 95% CI: 1.1 to 16.6;p ¼ 0.04) and almost a 10-fold increase in risk from 2




FIGURE 3 Prediction Models

1.0

0.9 p = 0.046

p = 0.03

p < 0.001

Harr

ell’s

C-S

tatis

tic

% V

A-Fr

ee S

urvi

val

0.8

0.7

0.6Model 1 Model 2 Model 3

HR (95% CI)

8.1 (2.3-28.4)p = 0.001

8.1 (2.3-28.8)p = 0.001

3.9 (1.4-11.1)p = 0.01

4.7 (1.2-17.5)p = 0.02

4.7 (1.6-13.9)p = 0.005

1.4 (1.2-1.6)p < 0.001

High intexercise

T-waveinversion

LV mechdispersion

NRI

IDI

AIC 119.8

0.65 (p = 0.01)

0.13 (p = 0.008)

115.9

0.97 (p < 0.001)

0.19 (p = 0.009)

105.0

HR (95% CI) HR (95% CI)

0.75 0.80 0.87

100

80

60

40

20

0

0 4

Log Rank, p < 0.001

Years of Follow-Up8 12

44

No. at risk

25 7 138 22 5206

11 4

0 Risk Factors 1 Risk Factor2 Risk Factors 3 Risk Factors

Incremental value of combining risk markers from different categories to predict life-threatening ventricular arrhythmia in 117 patients with arrhythmogenic

cardiomyopathy (left panel), and Kaplan-Meier curves of survival free from life-threatening ventricular arrhythmia (right panel). AIC ¼ Akaike information criterion;

CI ¼ confidence interval; HR ¼ hazard ratio; IDI ¼ integrated diagnostic improvement; NRI ¼ net reclassification improvement; Model 1 ¼ only high-intensity exercise;

Model 2 ¼ high-intensity exercise and T-wave inversions; Model 3 ¼ high-intensity exercise; T-wave inversions, and LV mechanical dispersion.


1383

to 3 risk factors (HR: 9.4, 95% CI: 2.3 to 37.8;p ¼ 0.002) (Figure 3, right panel).

The results of the final model were similar incompeting-risk regression (Online Table 3). Further-more, the model performed well also when excludingall patients with previous syncope (Harrell C-statistic0.79 [95% CI: 0.57 to 1.00]), and LV mechanicaldispersion remained a predictor of ventriculararrhythmia (HR: 1.89, 95% CI: 1.03 to 3.48 by 10-msincrements; p ¼ 0.04).

DISCUSSION

This is the first study following patients with AC withno previous life-threatening ventricular arrhythmiaprospectively until their first event. The incidence oflife-threatening ventricular arrhythmia in the totalpopulation was 22% at 5 years of follow-up, high-lighting the importance of continuous follow-up and

risk stratification. High-intensity exercise, TWI in ECG,and greater LV mechanical dispersion from echocar-diography were the strongest risk markers, and thecombination of these improved prediction of risksignificantly. Patients with all 3 risk factors had almost10-fold risk compared with those who had 2 risk fac-tors, indicating that a primary preventive ICD may beappropriate. However, patients with no risk factors oronly one risk factor had very low risk, suggesting thatlonger follow-up intervals are sufficient.

INCIDENCE OF LIFE-THREATENING VENTRICULAR

ARRHYTHMIA. The 5-year incidence of first-time life-threatening ventricular arrhythmia of 22% in ourstudy is in line with previous reports (16). The ma-jority of patients with such events were probands,and the higher risk of these compared with familymembers is well known (7,17). The lower incidencerate in family members confirmed a more benign




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prognosis (18) but still the need for risk stratificationand clinical follow-up of these patients.

PROGNOSTIC VALUE OF PARAMETERS AT INCLUSION.

This is the first prospective report of the harmful ef-fect of high-intensity exercise in patients with AC,confirming the strong association between expressionof disease and exercise (8,19). Syncope has also beenreported as a risk marker in previous studies (1,16,18).Patients with syncope at inclusion may have hadunrecognized ventricular tachycardia but wereincluded in this primary prevention population inline with the clinical management recommendations(1). In the adjusted statistical model, syncope was notan independent predictor when combined with pro-band status, reflecting a covariation with many pro-bands with syncope at inclusion. Status as mutationpositive was a marker of favorable arrhythmicoutcome, which is explained by the high number ofmutation positive family members with mild diseasewithout ventricular arrhythmia rather than a protec-tive effect of pathogenic mutations. The presence ofdepolarization abnormalities—that is, epsilon waveand abnormal SAECG—was not associated with sub-sequent life-threatening ventricular arrhythmia. Thisis in line with the limited risk prediction value ofepsilon waves (1). The prognostic value of major cri-terion TWI has been described previously in a longi-tudinal cohort study (7) and was confirmed in ourstudy.

All assessed echocardiographic parameters werepredictors of adverse arrhythmic outcome, high-lighting the fact that when structural changes areevident by imaging techniques, risk of life-threateningventricular arrhythmia is increased. LV mechanicaldispersion was a strong risk marker for arrhythmicevents. This is noteworthy, as conventional parame-ters of LV function have been reported to be spareduntil late stages of conventional AC phenotypes (20)and affected earlier only in a LV selective phenotype(21). Our finding underlined the fact that AC is abiventricular disease, also supported by previouslongitudinal studies (22,23). LV mechanical dispersionhas been reported as a marker of ventricular arrhyth-mias in other conditions by our group (4,24) andindependent groups (25,26), although others have notreported added benefit in prediction of risk (27). Thesediverging results may be explained by differentmethodologies and heterogeneous study populationsand illustrates the need for further research.

We have previously demonstrated that RVmechanical dispersion is a marker of previousarrhythmic events in smaller cross-sectional AC

cohorts (5,14). RV mechanical dispersion was a goodpredictor of ventricular arrhythmia in the currentstudy, but LV mechanical dispersion had higher C-statistic and was retained in the risk-predictionmodel. RVLS was also a strong risk predictor, andadding LV mechanical dispersion to RVLS improvedrisk reclassification, underlining the importance ofbiventricular assessment in AC patients.

As expected, lower RVEF, the presence of RV wall-contraction abnormalities, or RV aneurysms by CMRwere predictors of life-threatening ventriculararrhythmia. Furthermore, increased LV end-diastolicvolume was strongly associated with events, whichmay reflect both LV disease penetrance and physio-logical adaptations to exercise.

RISK PREDICTION MODEL AND ESTIMATES OF

RISK. The risk-prediction model improved by eachadded modality. This emphasized the importance ofmultimodality evaluation in these patients not onlyfor diagnostic purposes but also for risk stratification.Patients with 1 or no risk factors from the final modelhad a relatively benign arrhythmic prognosis, illus-trated by long estimated time to life-threateningventricular arrhythmia. This indicates that personspresenting with low risk can be identified andpossibly that appropriate modifications—for example,exercise restriction—can be made at an early stage.

Fulfilling 2 or more risk factors was associated withsignificantly worse prognosis. The worst prognosiswas seen in patients with all 3 risk factors, in which allexperienced life-threatening ventricular arrhythmiawithin 2 years. This could indicate that patients withmore than 1 risk factor could benefit from a primarypreventive ICD, but it should be confirmed in aseparate prospective cohort and balanced against ICDcomplication rates and patient inconvenience. One in3 patients with primary preventive ICD receivedappropriate shock therapy during follow-up, and 1 in10 patients without ICD experienced sustained VT.This suggested that the ICD selection was reasonablebut not optimal. However, cardiac arrest did notoccur in any patient during follow-up, meaning thatthe purpose of primary preventive ICD treatment wasfulfilled. This goal may be easier to obtain whenconsidering the risk factors we have described.

CLINICAL IMPLICATIONS

This was the first prospective study highlighting theimportance of assessing history of high-intensity ex-ercise together with ECG and cardiac imaging foroptimal prediction of risk in AC. Fulfilling 2 riskfactors was associated with a 4-fold increased risk of

PERSPECTIVES

COMPETENCY IN MEDICAL KNOWLEDGE: Patients with

arrhythmogenic cardiomyopathy have high risk of life-

threatening ventricular arrhythmia. Management of patients

presenting without arrhythmia is challenging. This study

demonstrated that parameters from clinical characteristics,

electrocardiogram, and cardiac imaging had independent and

incremental value as predictors of first-time life-threatening

ventricular arrhythmia in this patient group.

TRANSLATIONAL OUTLOOK: Recognition of patients at risk

of life-threatening ventricular arrhythmia is vital in the man-

agement of patients with arrhythmogenic cardiomyopathy. An

increasing proportion of patients are identified through increased

awareness of disease and genetic screening. It could be helpful

to consider exercise intensity, right precordial T-wave inversions,

and left ventricular mechanical dispersion when selecting pa-

tients with arrhythmogenic cardiomyopathy to receive primary

prevention implantable cardioverter-defibrillator therapy.


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life-threatening ventricular arrhythmia and shouldtrigger consideration for primary preventive ICD.Patients with all 3 risk factors had the worstarrhythmic outcome, and primary preventive ICDmay be warranted.

STUDY LIMITATIONS. The relatively low sample sizeand limited number of endpoints were the biggestlimitations of the current study. The single-centerdesign limited the external validity. Patients withprimary preventive ICD had continuous rhythmmonitoring and thus had greater chance of recog-nizing arrhythmic events than those without contin-uous rhythm registration. The current Task Forcecriteria (2) were applied retrospectively to patientsdiagnosed before 2010. CMR was only available in asubset of patients with a time delay and may havebeen subject to selection bias. Pathogenic mutationsin the plakophillin-2 gene were abundant in our studypopulation, and results may not be generalizable toAC populations with other dominating mutations. LVmechanical dispersion is dependent on temporalresolution and should only be used as a global mea-sure. The threshold of >45 ms found to predict life-threatening ventricular arrhythmia in the currentstudy should be confirmed in a separate cohort.

CONCLUSIONS

Patients with AC presenting without documentedventricular arrhythmia had 1-, 2-, and 5-year inci-dence of serious arrhythmic events of 6%, 9%, and22% during follow-up. History of high-intensity ex-ercise, T-wave inversions on ECG, and greaterechocardiographic LV mechanical dispersion werestrong predictors of life-threatening ventricular

arrhythmia with incremental prognostic value. Pa-tients with no risk factors had excellent prognoses,whereas fulfilling all risk factors increased the riskdramatically to 50% within 1.2 years. These findingsmay help decisions on primary preventive ICDtreatment.

ADDRESS FOR CORRESPONDENCE: Dr. Kristina H.Haugaa, Department of Cardiology, Oslo UniversityHospital, Rikshospitalet, Sognsvannsveien 20, 0372Oslo, Norway / P.O. Box 4950 Nydalen, 0424 Oslo,Norway. E-mail: [email protected].

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KEY WORDS arrhythmogeniccardiomyopathy, ARVC, ventriculararrhythmia, prediction, strainechocardiography

APPENDIX For supplemental tables, pleasesee the online version of this paper.





































































prediction of life-threatening ventricular arrhythmia in

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