APPENDIX
Figure 1. ECG in the Patient with Normal Baseline Electrical Evaluation and Abnormal
CMR. ECG at presentation of this 38 year old female mutation carrier showed T-wave
inversion in leads V1 and V3. This pattern was consistent during follow-up. Abbreviations:
CMR: cardiac magnetic resonance, ECG: electrocardiogram.
1
Table 1. Revised Task Force Criteria for ECG, Holter and CMR*
ECG / Holter monitoring
Cardiac Magnetic Resonance
Repolarization criteria
Structural alterations or cardiac dysfunction
Major
Major
T-wave inversion V1-3 or beyond
Minor
T-wave inversion V1-2
Regional RV akinesia, dyskinesia, aneurysm†
or dyssynchronous contraction
and 1 of the following:
- RV end-diastolic volume / BSA
T-wave inversion V1-4 in presence of
RBBB
≥110 mL/m2 (male) or ≥100 mL/ m2 (female)
- RV ejection fraction ≤40%
Depolarization criteria
Major
Epsilon waves in V1-3
Minor
Minor
Regional RV akinesia, dyskinesia, aneurysm†
Terminal activation duration ≥ 55ms in V1-3 or dyssynchronous contraction
Arrhythmia criteria
Major
and 1 of the following:
- RV end-diastolic volume / BSA
Non-sustained or sustained VT of LBBB
≥100 to <100 mL/m2 (male) or ≥90 to <100
morphology with superior axis
mL/ m2 (female)
Minor
- RV ejection fraction >40 to ≤45%
≥ 500 PVCs / 24 hours
Non-sustained or sustained VT of LBBB
morphology with inferior axis or unknown
axis
2
* In our study, electrical abnormalities were considered present in case ECG and/or Holter
abnormalities were present, and CMR was considered abnormal in case any criterion for
CMR was present. † Aneurysms were defined as regions with both systolic and diastolic
bulging. Abbreviations: BSA: body surface area, CMR: cardiac magnetic resonance, ECG:
electrocardiogram, LV: left ventricular, PVC: premature ventricular complex, RBBB: right
bundle branch block, RV: right ventricular, VT: ventricular tachycardia
3
Table 2. Definitions of Clinical and ECG Variables Employed in the Study
Term
Definition
Death of cardiac origin that occurred unexpectedly
Sudden Cardiac death
within 1 hour of the onset of new symptoms or a death
that was unwitnessed and unexpected
An event as described above, that is reversed, usually by
Aborted sudden cardiac death
cardio-pulmonary resuscitation and/or defibrillation or
cardioversion
Sustained ventricular tachycardia
Ventricular tachycardia lasting more than 30 seconds
ICD shock or antitachycardia overdrive pacing delivered
Appropriate ICD Therapy
in response to a ventricular tachyarrhythmia and
documented by stored intracardiac ECG data
Electrical storm
Occurrence of ≥ 3 episodes of VT/ VF in a 24-h period
≥ 3 consecutive ventricular premature beats with a rate
>100 beats/min, lasting <30 s, which was documented
Nonsustained VT
during exercise testing, loop monitoring, or 24-h Holter
monitoring
Distinct waves of small amplitude that occupy the ST
Epsilon wave
segment in the right precordial leads and are distinct
from the QRS complex
The longest value in V1–V3, from the nadir of the S
Terminal Activation Delay
wave to the end of all depolarization deflections.
Considered abnormal when >55 ms
Complete Right bundle branch
QRSd >0.12 s, secondary R wave in right precordial
block
leads, and wide S wave in leads I and V6
4
Abbreviations: ICD: Implantable Cardioverter-Defibrillator; VT: ventricular tachycardia; VF:
ventricular fibrillation
5
Table 3. List of Mutations Identified in the Study Population
Gene; n (%)
n
Amino Acid Change
Nucleotide Change
PKP2; 57 (83)
7
V548fsX562
1643delG
7
IVS10-1G->C
2146-1G->C
4
A733fsX740
2197_2202delinsG
4
Mutant splice product
2489+1G>A
3
G828G
2484C>T
3
V837fsX930
2509delA
3
P672fsX683
2013delC
3
W538X
1613G>A
3
R79X
235C>T
3
R413X
1237C>T
2
F424S
1271T>C
2
S50fsX110
148_151delACAG
2
Q74fsX85
218dupG
2
V587I
Nt1759G>A
2
Mutant splice product
1378+1G>C
2
Q617X
1849C>T
2
fsX350
968_971delAGGC
1
S406fsX409
1211dupT
1
S615F
1844C>T
1
Trp538X
1613G>A
2
E422K
1264G>A
1
Arg2160stop
6478C>T
DSP; 5 (7)
6
1
Arg160Ter
476C>T
1
Gln51Stop
151C>T
2
Thr335Ala
1003A>G
1
R49H
146 G>A
1
T1047R
3140C>G
1
G220R
658G>A
Compound/Digenic 1
Mutant splice product (DSG2)
523+2T>C (DSG2), K346del
Heterozygote; 2 (3)
+ 1038_1040delGAA (DSG2)
(DSG2)
Glu426Lys (DSC2) +
1276G>A (DSC2) + 4693C>G
Pro1565Ala (RYR2)
(RYR2)
DSG2; 4 (6)
DSC2; 1 (1)
1
Abbreviations: DSC2: Desmocollin-2, DSG2: desmoglein-2, DSP: Desmoplakin, PKP2:
Plakophilin-2, RYR2: Ryanodine Receptor-2
7
Table 4. ICD Characteristics and Programming in the Study Population.
Overall
ICD carriers
ICD carrier with
(n=26)
without appropriate
appropriate
intervention (n=16)
intervention
p-value
(n=10)*
Age at implantation (yrs)
29.7 ± 12.6
33.2 ± 14.9
24.3 ± 5.4
0.047
Dual chamber
5 (19)
2 (13)
3 (30)
NS
Primary prevention
22 (85)
15 (94)
7 (70)
NS
Rate cut-off (bpm)
190 ± 13
191 ± 15
189 ± 12
NS
Time to appropriate
1.1 ± 1.8
-
1.1 ± 1.8
-
Electrical storm
3 (12)
0 (0)
3 (30)
0.020
Inappropriate intervention
5 (19)
3 (19)
2 (20)
NS
Complications
4 (15)
2 (13)
2 (20)
NS
intervention (yrs)
* For 7 patients, the appropriate ICD intervention was the first arrhythmic event.
Additionally, three patients received an ICD for secondary prevention after spontaneous
VT/VF, and experienced appropriate therapy during follow-up.
Abbreviations: ICD: implantable cardioverter-defibrillator, NS: non significant, VF:
ventricular fibrillation, VT: ventricular tachycardia.
8