ORIGINAL RESEARCH
Prediction of Life-Threatening
Ventricular Arrhythmia in Patients With Arrhythmogenic Cardiomyopathy
A Primary Prevention Cohort Study
Øyvind H. Lie, MD,a,b,cChristine Rootwelt-Norberg, MD,a,bLars A. Dejgaard, MD,a,b,cIda Skrinde Leren, MD, PHD,a,b,c Mathis K. Stokke, MD, PHD,a,b,cThor Edvardsen, MD, PHD,a,b,c,dKristina H. Haugaa, MD, PHDa,b,c,d
ABSTRACT
OBJECTIVESThis study aimed to identify clinical, electrocardiographic (ECG) and cardiac imaging predictors offirst- time life-threatening ventricular arrhythmia in patients with arrhythmogenic cardiomyopathy (AC).
BACKGROUNDThe role of clinical, electrocardiographic, and cardiac imaging parameters in risk stratification of pa- tients without ventricular arrhythmia is unclear.
METHODSWe followed consecutive AC probands and mutation-positive family members with no documented ven- tricular arrhythmia from time of diagnosis tofirst 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.
RESULTSWe included 117 patients (29% probands, 50% female, age 4017 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$V3, and greater LV mechanical dispersion were the strongest risk markers (adjusted hazard ratio [HR]: 4.7 [95% confidence in- terval (CI): 1.2 to 17.5]; p¼0.02, 4.7 [95% CI: 1.6 to 13.9]; p¼0.005), and 1.4 [95% CI: 1.2 to 1.6] by 10-ms increments;
p<0.001, respectively). Median arrhythmia-free survival in patients with all risk factors was 1.2 (95% CI: 0.4 to 1.9) years, compared with an estimated 12.0 (95% CI: 11.5 to 12.5) years in patients without any risk factors.
CONCLUSIONSHistory of high-intensity exercise, electrocardiographic T-wave inversions$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 cardiacdesmosomes, resulting infibrofatty replacement and subsequent structural and functional alterations of the right ventricle (RV) and left ventricle (LV). The disease is characterized by high risk of life-
ISSN 1936-878X https://doi.org/10.1016/j.jcmg.2018.05.017
From theaDepartment of Cardiology, Oslo University Hospital, Rikshospitalet, Oslo, Norway;bCenter for Cardiological Innovation, Oslo University Hospital, Rikshospitalet, Oslo, Norway;cInstitute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; and thedInstitute for Surgical Research, University of Oslo, Oslo, Norway. This research was supported by a public research grant from South-Eastern Norway Health Authority and the Center for Cardiological Innovation, which is supported by the Norwegian Research Council. Drs. Haugaa and Edvardsen have licensed a patent of mechanical dispersion.
All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Manuscript received December 12, 2017; revised manuscript received April 13, 2018, accepted May 24, 2018.
threatening ventricular arrhythmia and car- diac arrest in presumed healthy young persons. The management of patients with AC presenting with life-threatening ventricu- lar arrhythmia is well established, with placement of implantable cardioverter- defibrillators (ICDs) as a recommended strat- egy (1). Management of patients presenting without life-threatening events is less well defined, and risk stratification and selection of patients to receive primary preventive ICDs is challenging.
The diagnosis of AC is based on a complex set of criteria according to the revised Task Force Criteria (TFC) of 2010(2), in which electrocardiogram (ECG) and cardiac imaging are central elements. Ad- vances in echocardiography have provided sensitive and 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 as part of a multimodality imaging approach in AC(6), but prospective studies on prognostic value are lack- ing. Furthermore, implementation of cascade genetic testing has shifted the AC population toward more asymptomatic mutation-positive family members.
These individuals are at lower risk of arrhythmic events than probands but should still be risk stratified and considered for primary preventive ICD(7). Prog- nostic markers in this population are largely unde- fined. We aimed to explore incidence and predictors offirst-time life-threatening ventricular arrhythmia in a 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, were evaluated consecutively for inclusion in a primary prevention cohort study. Probands underwent ge- netic testing as described previously(8), and cascade genetic screening was performed in family members of mutation positive probands. Mutation negative probands 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 was defined as sustained ventricular tachycardia—runs of consecutive 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 consecutive runs 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 activities were assigned intensity levels on the basis of the Compendium of Physical Activity of 2011(10). High- intensity exercise was defined as physical activity>6 metabolic equivalents performed regularly during a minimum of 3 consecutive years before inclusion(11).
Patients with life-threatening event at or prior to first contact and patients with cardiopulmonary co- morbidity were excluded. Time tofirst life-threatening ventricular arrhythmia was recorded prospectively from time of diagnosis of AC or from time of first echocardiography 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 October 1, 2017. Written informed consent was given by all included patients. The study complied with the decla- ration of Helsinki and was approved by the Regional Medical Ethics Committee of South-Eastern Norway.
ELECTROCARDIOGRAM. Twelve-lead ECG was ob- tained at inclusion (MAC 1200 or MAC 5000, GE Medical 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 terminal activation 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 examined with echocardiography at inclusion (Vivid 7, E9 or E95, GE, Vingmed, Horten, Norway), and datasets were analyzed offline (EchoPac 201, GE, Vingmed) by 2 independent observers blinded to clinical and ECG data. LV ejection fraction (LVEF) was assessed by the biplane Simpson’s method. The LV global longitudi- nal strain (GLS) was derived from speckle tracking analyses on 2-dimensional (2D) gray-scale image loops with>50 frames/s from the 3 apical views and expressed as the average peak systolic strain in a 16-segment LV model (13). LV mechanical disper- sion was defined as the standard deviation of time from Q/R on surface ECG to peak negative strain in 16 LV segments(4)(Figure 1, upper left panels).
The RV function was assessed by the RV fractional area change (FAC), tricuspid annular plane systolic excursion (TAPSE), and RV longitudinal strain (RVLS), defined as the average peak systolic strain in 3 free-wall RV segments (Figure 1, upper right panel).
RV mechanical dispersion (RVMD) was defined as the
SEE PAGE 1387 A B B R E V I A T I O N S
A N D A C R O N Y M S
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
standard deviation from the time of Q/R on ECG to peak negative strain in 6 RV segments, including 3 septal segments(5). RV dimension measures included proximal diameter of RV outflow tract (RVOT) from parasternal 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 magnetic resonance imaging (CMR) was performed as previ- ously reported(15)on clinical indication in a subset of patients at inclusion and evaluated for the presence of 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’st-test, chi-square test, Fisher’s exact test, or Mann-Whitney U test, as appropriate. Incidence of life-threatening ventricular arrhythmia was calculated by dividing number of events by number of eligible patients at 1, 2, and 5 years of 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 with maximum 3 covariates, retaining the 3 parameters with the highest Harrell’s C-statistic in case of multiple possible confounders: 1) clinical characteristics: high- intensity exercise, probands status and history of
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). 2CH¼apical 2-chamber view; 4CH¼apical 4-chamber view; APLAX¼apical long axis view; AVC¼aortic valve closure; ECG¼electrocardiogram; LV¼left ventricle; RV¼right ventricle.
syncope; 2) electrocardiography: major TWI and sex; 3) echocardiography: LV mechanical dispersion, RVLS, and sex; and 4) CMR: LVEDVi, RVEF, and sex. The optimal cutoff values of continuous variable were defined 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 added to a stepwise Cox regression model. The incremental value of added parameters in the prediction models were assessed by reclassification analysis by inte- grated diagnostic improvement (IDI) and continuous net reclassification improvement (NRI), and the C- statistics for prediction models were compared. The Akaike information criterion (AIC) was estimated for the risk models. Kaplan-Meier analyses of estimated ventricular arrhythmia-free survival for the risk fac- tors were conducted, dichotomizing continuous risk markers at the optimal cutoff value. Competing-risk regression was conducted to assess the impact of competing 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.Of 188 patients presenting at our center with definite,
borderline, or possible AC diagnosis, 7 (4%) were excluded due to concomitant heart disease, 61 (34%) were excluded due to life-threatening ventricular arrhythmia 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 (n¼18, 53%), palpitations (n¼13, 38%), and chest pain (n¼12, 35%).
During 4.2 years (IQR: 2.4 to 7.4 years) of follow- up, 21 (18%) patients received primary preventive ICD. Life-threatening ventricular arrhythmia occurred in 18 (15%) patients (14 probands, and 4 family members) after 2.0 years (IQR: 0.5 to 3.5 years) of follow-up (Table 1); as documented sustained ventricular tachycardia in 11 (6 on clinical 12-lead ECG, 4 below therapy zone on ICD recordings, and 1 on 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 the incidence rate was 3.1 (95% confidence interval [CI]:
1.9 to 5.0) per 100 patient years. Analyses of probands separately showed 1-, 2-, and 5-year incidence of 21%, 25%, and 57%, respectively, and an incidence rate of 10.9 (95% CI: 6.3 to 18.8) per 100 patient years. Four (5%) family members experienced life-threatening ventricular arrhythmias after 3.8 years (IQR: 1.3 to
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 (N¼117) No VA (n¼99) VA (n¼18) p Value Adjusted HR (95% CI) p Value
Age, yrs 4017 401 8 3916 0.89
BSA, m2 2.00.2 2.00.2 2.00.2 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 meanSD or n (%), unless otherwise stated. The p values are calculated by Student’st-test, chi-square test, or Fischer’s exact test as appropriate. Adjusted HR by multivariable 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-statistic from univariable Cox regression.
AA¼anti-arrhythmic; AC¼arrhythmogenic cardiomyopathy; BSA¼body surface area; DSC¼desmocollin-gene; DSG¼desmoglein-gene; DSP¼desmoplakin-gene;
NSVT¼nonsustained ventricular tachycardia; PKP2¼plakophillin 2-gene; VA¼life-threatening ventricular arrhythmia.
8.1 years) of follow-up. Separate analyses of family members 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<0.001 compared with probands). Two patients were censored by noncardiac death and 1 by cardiac transplantation.
CLINICAL PREDICTORS OF LIFE-THREATENING VENTRICULAR ARRHYTHMIA.Male sex, history of high-intensity exercise, absence of AC-related muta- tion, proband status, and previous syncope were predictors in univariable analyses of clinical markers (Table 1). High-intensity exercise was more prevalent
among male than among female patients (53% vs.
21%; p¼0.001).
ECG PREDICTORS OF LIFE-THREATENING VENTRICULAR ARRHYTHMIA.ECG and SAECG were performed at the same day as echocardiography. Major TWI was the only predictor on ECG (Table 2, Figure 2, mid panel).
SAECG was performed in 100 (91%) patients without RBBB, of whom 48 (48%) had abnormalfindings (47 had fQRSd>114 ms, 35 (35%) had RMS<20mV, and 35 (35%) patients had HFLA>38 ms).
CARDIAC IMAGING PREDICTORS OF LIFE-THREATENING VENTRICULAR ARRHYTHMIA.Four patients (3%) had their first echocardiographies performed on older
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 (N¼117) No VA (n¼99) VA (n¼18) 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 11513 11514 1179 0.58
HFLA, ms 3712 3713 378 0.93
RMS,mV 3217 3317 2717 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, % (n¼115) 577 585 5212 0.001 *
GLS, % (n¼110) 19.33.0 19.92.4 16.64.1 <0.001 *
LVMD, ms†(n¼110) 4118 3713 6225 <0.001 1.3 (1.1-1.5) 0.005
RVD, mm 407 396 457 <0.001 *
RV FAC, % (n¼111) 429 439 348 <0.001 *
RVLS, % (n¼108) 24.86.4 26.15.8 18.65.4 <0.001 1.1 (1.0-1.2) <0.05
RVMD, ms (n¼108) 3519 3317 4920 <0.001 *
RVOT, mm 347 336 388 0.003 *
TAPSE, mm (n¼114) 215 215 175 0.003 *
CMR N¼88 n¼72 n¼16
LGE 11 (13) 7 (10) 4 (27) 0.08 *
LVEDVi, ml/m2 8824 8522 11422 0.007 1.1 (1.0-1.1) <0.05
LVEF 578 588 518 0.04 *
RVEDVi, ml/m2 9935 9834 10642 0.64
RVEF 4911 5011 378 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 meanSD, unless otherwise stated. The p values are calculated by Student’st-test, chi-square test, or Fischer’s exact test as appropriate. Separate multivariable Cox regression per category together with patient sex as possible confounder. *From echocardiography and CMR, only the parameters with the largest Harrell’s C-statistic from LV and RV in univariable Cox regression were retained in multivariable analysis, to minimize overfitting.†Hazard ratio by 10-ms increments.
AC¼arrhythmogenic cardiomyopathy; CMR¼cardiac magnetic resonance; ECG¼electrocardiogram; EF¼ejection fraction; GLS¼global longitudinal strain; HFLA¼high frequency low amplitude duration below 40mV; LGE¼late gadolinium enhancement; LV¼left ventricle; LVEDVi¼LV end-diastolic volume indexed; LVIDd¼LV internal diameter in diastole; LVMD¼LV mechanical dispersion; RMS¼root mean square voltage duringfinal 40 ms; RV¼right ventricle; RVD¼RV basal diameter; RVEDVi¼RV end- diastolic volume indexed; RV FAC¼RV fractional area change; RVLS¼RV longitudinal strain; RVMD¼RV mechanical dispersion; RVOT¼RV outflow tract diameter; SAECG¼ signal-averaged electrocardiogram; TAD¼terminal activation duration; TAPSE¼tricuspid annulus plane systolic excursion; TWI¼T-wave inversion; VA¼life-threatening ventricular arrhythmia.
scanners, and time to event was recorded from their first echocardiographies on a GE Vivid 7 or newer scanners. LV speckle tracking analyses were feasible in 110 patients (frame rate 63 [IQR: 56 to 69] and RV in 108 patients (frame rate 65 [IQR: 56 to 73]). Echocar- diographic parameters of cardiac structure and func- tion were consistently worse in patients who later experienced life-threatening ventricular arrhythmias (Table 2). This was evident both in probands and mutation-positive family members (Online Table 1A and 1B, respectively). LV mechanical dispersion and RVLS had the highest Harrell’s C-statistic (0.84 and 0.81, respectively) and were independent predictors in 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 mechanical dispersion 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 prediction model with known GLS, LV mechanical dispersion improved the risk reclassification (Online Table 2).
CMR was available in 88 (75%) patients (35% pro- bands, 49% female, age 3816 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 the highest Harrell’s C-statistic from clinical characteris- tics, ECG, and cardiac imaging were added to a Cox regression model (Figure 3, left panel). Adding TWI to high-intensity exercise significantly increased Har- rell’s C-statistic and improved risk reclassification.
Adding LV mechanical dispersion to the combination of high-intensity exercise and TWI further improved C-statistic significantly and improved risk reclassifi- cation (Figure 3, left panel). Estimated survival free from life-threatening ventricular arrhythmia in pa- tients with all 3 risk factors was only 1.2 (95% CI: 0.4 to 1.9) years compared with 12.0 (95% CI: 11.5 to 12.5) years in patients without any risk factors. All patients with 3 risk factors experienced life-threatening ven- tricular arrhythmias within 2 years, whereas only 1 of 44 patients without any risk factors experienced the endpoint during 218 patient years of follow-up. There was no significant increase in risk from no risk factors to 1 risk factor, but a 4-fold increase from 1 to 2 risk factors (hazard ratio [HR]: 4.1, 95% CI: 1.1 to 16.6;
p¼0.04) and almost a 10-fold increase in risk from 2
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 8
Years of Follow-Up 12
100
LV Mechanical Dispersion
80 60 40 20 0
0
Log Rank, p < 0.001
4 8
Years of Follow-Up 12 100
High-Intensity Exercise
80 60
% VA-Free Survival
40 20 0
0
Log Rank, p < 0.001
4 8
Years of Follow-Up 12
≤6 METs >6 METs TWI <V3 TWI ≥V3 MD ≤45 ms MD >45 ms
94 55 14
23 9 4
1 73 41 11
37 18 4
1 No. at risk
71 41 11
42 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. MD¼left ventricular mechanical dispersion; METs¼metabolic equivalents; TWI¼T-wave inversion; VA¼life-threatening ventricular arrhythmia.
to 3 risk factors (HR: 9.4, 95% CI: 2.3 to 37.8;
p¼0.002) (Figure 3, right panel).
The results of the final model were similar in competing-risk regression (Online Table 3). Further- more, the model performed well also when excluding all patients with previous syncope (Harrell C-statistic 0.79 [95% CI: 0.57 to 1.00]), and LV mechanical dispersion remained a predictor of ventricular arrhythmia (HR: 1.89, 95% CI: 1.03 to 3.48 by 10-ms increments; p¼0.04).
DISCUSSION
This is thefirst study following patients with AC with no previous life-threatening ventricular arrhythmia prospectively until theirfirst event. The incidence of life-threatening ventricular arrhythmia in the total population 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 the combination of these improved prediction of risk significantly. Patients with all 3 risk factors had almost 10-fold risk compared with those who had 2 risk fac- tors, indicating that a primary preventive ICD may be appropriate. However, patients with no risk factors or only one risk factor had very low risk, suggesting that longer follow-up intervals are sufficient.
INCIDENCE OF LIFE-THREATENING VENTRICULAR ARRHYTHMIA. The 5-year incidence offirst-time life- threatening ventricular arrhythmia of 22% in our study 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 family members is well known (7,17). The lower incidence rate in family members confirmed a more benign
FIGURE 3 Prediction Models 1.0
0.9 p = 0.046
p = 0.03 p < 0.001
Harrell’s C-Statistic % VA-Free Survival
0.8
0.7
0.6
Model 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 int
exercise T-wave inversion LV mech dispersion 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-Up
8 12
44 No. at risk
25 7 1
38 22 5
20 6
11 4
0 Risk Factors 1 Risk Factor 2 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). AIC¼Akaike information criterion;
CI¼confidence interval; HR¼hazard ratio; IDI¼integrated diagnostic improvement; NRI¼net reclassification improvement; Model 1¼only high-intensity exercise;
Model 2¼high-intensity exercise and T-wave inversions; Model 3¼high-intensity exercise; T-wave inversions, and LV mechanical dispersion.
prognosis(18)but still the need for risk stratification and clinical follow-up of these patients.
PROGNOSTIC VALUE OF PARAMETERS AT INCLUSION.
This is thefirst prospective report of the harmful ef- fect of high-intensity exercise in patients with AC, confirming the strong association between expression of disease and exercise(8,19). Syncope has also been reported as a risk marker in previous studies(1,16,18).
Patients with syncope at inclusion may have had unrecognized ventricular tachycardia but were included in this primary prevention population in line with the clinical management recommendations (1). In the adjusted statistical model, syncope was not an independent predictor when combined with pro- band status, reflecting a covariation with many pro- bands with syncope at inclusion. Status as mutation positive was a marker of favorable arrhythmic outcome, which is explained by the high number of mutation positive family members with mild disease without ventricular arrhythmia rather than a protec- tive effect of pathogenic mutations. The presence of depolarization abnormalities—that is, epsilon wave and abnormal SAECG—was not associated with sub- sequent life-threatening ventricular arrhythmia. This is in line with the limited risk prediction value of epsilon 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 our study.
All assessed echocardiographic parameters were predictors of adverse arrhythmic outcome, high- lighting the fact that when structural changes are evident by imaging techniques, risk of life-threatening ventricular arrhythmia is increased. LV mechanical dispersion was a strong risk marker for arrhythmic events. This is noteworthy, as conventional parame- ters of LV function have been reported to be spared until 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 a biventricular disease, also supported by previous longitudinal studies(22,23). LV mechanical dispersion has been reported as a marker of ventricular arrhyth- mias in other conditions by our group (4,24) and independent groups(25,26), although others have not reported added benefit in prediction of risk(27). These diverging results may be explained by different methodologies and heterogeneous study populations and illustrates the need for further research.
We have previously demonstrated that RV mechanical dispersion is a marker of previous arrhythmic events in smaller cross-sectional AC
cohorts(5,14). RV mechanical dispersion was a good predictor of ventricular arrhythmia in the current study, but LV mechanical dispersion had higher C- statistic and was retained in the risk-prediction model. RVLS was also a strong risk predictor, and adding LV mechanical dispersion to RVLS improved risk reclassification, underlining the importance of biventricular assessment in AC patients.
As expected, lower RVEF, the presence of RV wall- contraction abnormalities, or RV aneurysms by CMR were predictors of life-threatening ventricular arrhythmia. Furthermore, increased LV end-diastolic volume was strongly associated with events, which may reflect both LV disease penetrance and physio- logical adaptations to exercise.
RISK PREDICTION MODEL AND ESTIMATES OF RISK. The risk-prediction model improved by each added modality. This emphasized the importance of multimodality evaluation in these patients not only for diagnostic purposes but also for risk stratification.
Patients with 1 or no risk factors from thefinal model had a relatively benign arrhythmic prognosis, illus- trated by long estimated time to life-threatening ventricular arrhythmia. This indicates that persons presenting with low risk can be identified and possibly that appropriate modifications—for example, exercise restriction—can be made at an early stage.
Fulfilling 2 or more risk factors was associated with significantly worse prognosis. The worst prognosis was seen in patients with all 3 risk factors, in which all experienced life-threatening ventricular arrhythmia within 2 years. This could indicate that patients with more than 1 risk factor could benefit from a primary preventive ICD, but it should be confirmed in a separate prospective cohort and balanced against ICD complication rates and patient inconvenience. One in 3 patients with primary preventive ICD received appropriate shock therapy during follow-up, and 1 in 10 patients without ICD experienced sustained VT.
This suggested that the ICD selection was reasonable but not optimal. However, cardiac arrest did not occur in any patient during follow-up, meaning that the purpose of primary preventive ICD treatment was fulfilled. This goal may be easier to obtain when considering the risk factors we have described.
CLINICAL IMPLICATIONS
This was thefirst prospective study highlighting the importance of assessing history of high-intensity ex- ercise together with ECG and cardiac imaging for optimal prediction of risk in AC. Fulfilling 2 risk factors was associated with a 4-fold increased risk of
life-threatening ventricular arrhythmia and should trigger consideration for primary preventive ICD.
Patients with all 3 risk factors had the worst arrhythmic outcome, and primary preventive ICD may be warranted.
STUDY LIMITATIONS.The relatively low sample size and limited number of endpoints were the biggest limitations of the current study. The single-center design limited the external validity. Patients with primary preventive ICD had continuous rhythm monitoring and thus had greater chance of recog- nizing arrhythmic events than those without contin- uous rhythm registration. The current Task Force criteria (2) were applied retrospectively to patients diagnosed before 2010. CMR was only available in a subset of patients with a time delay and may have been subject to selection bias. Pathogenic mutations in the plakophillin-2 gene were abundant in our study population, and results may not be generalizable to AC populations with other dominating mutations. LV mechanical dispersion is dependent on temporal resolution and should only be used as a global mea- sure. The threshold of>45 ms found to predict life- threatening ventricular arrhythmia in the current study should be confirmed in a separate cohort.
CONCLUSIONS
Patients with AC presenting without documented ventricular arrhythmia had 1-, 2-, and 5-year inci- dence of serious arrhythmic events of 6%, 9%, and 22% during follow-up. History of high-intensity ex- ercise, T-wave inversions on ECG, and greater echocardiographic LV mechanical dispersion were strong 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 risk dramatically to 50% within 1.2 years. Thesefindings may help decisions on primary preventive ICD treatment.
ADDRESS FOR CORRESPONDENCE: Dr. Kristina H.
Haugaa, Department of Cardiology, Oslo University Hospital, Rikshospitalet, Sognsvannsveien 20, 0372 Oslo, Norway / P.O. Box 4950 Nydalen, 0424 Oslo, Norway. E-mail:kristina.haugaa@medisin.uio.no.
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KEY WORDS arrhythmogenic cardiomyopathy, ARVC, ventricular arrhythmia, prediction, strain echocardiography
APPENDIX For supplemental tables, please see the online version of this paper.
